Substituted Sulfonamide Compounds

ABSTRACT

Substituted sulfonamide compounds corresponding to the formula I 
     
       
         
         
             
             
         
       
     
     wherein m, n, p, Q, R 1 , R 2 , R 3 , R 4 , X, Y and Z have the respective meanings defined herein, pharmaceutical compositions containing such compounds, a process for their preparation, and the use of such compounds for the treatment and/or inhibition of pain and other conditions mediated by bradykinin receptor 1 (B1R) and/or bradykinin receptor 2 (B2R).

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims priority from U.S. provisional patentapplication No. 61/021,809, filed Jan. 17, 2008 and from European patentapplication no. EP 08000840, also filed Jan. 17, 2008, the entiredisclosures of which are incorporated herein by reference.

BACKGROUND OF THE INVENTION

The present invention relates to substituted sulfonamide compounds,processes for their preparation, medicaments containing these compounds,and the use of substituted sulfonamide compounds for the preparation ofpharmaceutical compositions.

In contrast to the constitutive expression of the bradykinin 2 receptor(B2R) the bradykinin 1 receptor (B1R) is not expressed, or is onlyweakly expressed in most tissues. However, the expression of B1R can beinduced in various cells. For example, in the course of inflammatoryreactions there is a rapid and pronounced induction of B1R on neuronalcells but also on various peripheral cells such as fibroblasts,endothelial cells, granulocytes, macrophages and lymphocytes. In thecourse of inflammatory reactions there is thus a switch from a B2R to aB1R dominance on the involved cells. The cytokines interleukin-1 (IL-1)and tumour necrosis factor alpha (TNFα) (Passos et al. J. Immunol. 2004,172, 1839-1847) are significantly involved in this up-regulation. Afteractivation with specific ligands, B1R-expressing cells can thenthemselves secrete inflammation-promoting cytokines such as IL-6 andIL-8 (Hayashi et al. Eur. Respir. J. 2000, 16, 452-458). This leads tothe inflow of further inflammatory cells, e.g. neutrophilic granulocytes(Pesquero et al. PNAS 2000, 97, 8140-8145). Via these mechanisms thebradykinin B1R system can contribute to the chronic condition ofdiseases. This is confirmed by a number of animal experimentinvestigations (reviews in Leeb-Lundberg et al., Pharmacol Rev. 2005,57, 27-77 and Pesquero et al., Biol. Chem., 2006, 387, 119-126). Anenhanced expression of B1R is also found in humans, for example onenterocytes and macrophages in the affected tissue of patients sufferingfrom inflammatory intestinal diseases (Stadnicki et al. Am. J. Physio.Gastrointest. Liver Physiol. 2005, 289, G361-366) and on T lymphocytesof patients suffering from multiple sclerosis (Pratet et al., Neurology,1999, 53, 2087-2092) or an activation of the bradykinin B2R-B1R systemduring infections with Staphylococcus aureus (Bengtson et al., Blood2006, 108, 2055-2063). Infections with Staphylococcus aureus areresponsible for clinical conditions ranging from surface infections ofthe skin up to septic shock.

Due to the pathophysiological relationships outlined above, there is agreat therapeutic potential for the use of B1R antagonists in acute andin particular chronic-inflammatory diseases. These include diseases ofthe respiratory tract (bronchial asthma, allergies, COPD (chronicobstructive pulmonary disease), cystic fibrosis, etc.), inflammatoryintestinal diseases (ulcerative colitis, CD (Crohn's disease), etc.),neurological diseases (multiple sclerosis, neurodegeneration, etc.),inflammations of the skin (atopic dermatitis, psoriasis, bacterialinfections, etc.) and mucous membranes (M. Behcet, pelvitis,prostatitis), rheumatic diseases (rheumatoid arthritis, osteoarthritis,etc.), septic shock, and reperfusion syndrome (after heart attacks andstrokes).

In addition the bradykinin (receptor) system is also involved in theregulation of angiogenesis (potential as an angiogenesis inhibitor incancer and also macular degeneration of the eye) and B1R knockout miceare protected against the danger of becoming overweight due to aparticularly fat-rich diet (Pesquero et al., Biol. Chem. 2006, 387,119-126). B1R antagonists are therefore also suitable for treatingobesity.

B1R antagonists are in particular suitable for treating pain, inparticular inflammatory pain and neuropathic pain (Calixto et al. Br. J.Pharmacol 2004, 1-16), in this connection in particular diabeticneuropathy (Gabra et al., Biol. Chem. 2006, 387, 127-143). Furthermorethey are suitable for the treatment of migraine.

In the development of B1R modulators there is the problem however thatthe human and rat B1R receptors differ so greatly that many compoundsthat are good B1R modulators on the human receptor have only a pooraffinity or no affinity at all for the rat receptor. This significantlycomplicates animal pharmacological investigations since manyinvestigations are normally carried out on rats. If however a compoundhas no effect on the rat receptor, then neither the action nor sideeffects on rats can be investigated. This has already led to thecreation of transgenic animals with human B1 receptors for animalpharmacological investigations (Hess et al., Biol. Chem. 2006; 387(2):195-201). Working with transgenic animals is however more costly thanworking with unaltered animals. Since long-term toxicity investigationson rats are in particular part of the routine investigations in drugresearch and development however, these are not practicable if thecompound is ineffective on the receptor, and an important establishedtool for checking safety is therefore lacking in the development of suchcompounds. There is therefore a need for new B1R modulators, in whichconnection B1R modulators that bind to the rat receptor as well as tothe human receptor offer particular advantages.

SUMMARY OF THE INVENTION

An object of the present invention was accordingly to provide newcompounds that are suitable in particular as pharmacological activeconstituents in medicaments, preferably in medicaments for treatingdisorders or diseases that are at least partially mediated by B1Rreceptors.

This object has been achieved by the substituted sulfonamide compoundsaccording to the invention as described and claimed hereinafter.

The present invention provides substituted sulfonamide compoundscorresponding to formula I:

wherein

-   m and n each independently denote 0, 1 or 2;-   p denotes 1 or 2;-   Q denotes —O— or —CH₂—;-   X denotes N or CR⁵;-   Y denotes N or CR⁶;-   Z denotes N or CR⁷;-   R¹ denotes aryl, heteroaryl, or an aryl or heteroaryl group bonded    via a C₁₋₆-alkylene group;-   R² denotes H, C₁₋₆-alkyl, aryl, heteroaryl, or an aryl or heteroaryl    group bonded via a C₁₋₆-alkylene group, C₂₋₆-alkenylene group or    C₂₋₆-alkynylene group;-   R³ denotes H, C₁₋₆-alkyl, aryl, heteroaryl, or an aryl or heteroaryl    group bonded via a C₁₋₆-alkylene group, C₂₋₆-alkenylene group or    C₂₋₆-alkynylene group;-   R⁴ denotes H, halogen, CN, NO₂, C₁₋₆-alkyl, aryl, heteroaryl, or an    aryl or heteroaryl group bonded via a C₁₋₆-alkylene group,    C₂₋₆-alkenylene group or C₂₋₆-alkynylene group;-   R⁵, R⁶ and R⁷ each independently denote H, halogen, CN, C₁₋₆-alkyl,    —NH(C₁₋₆-alkyl), —N(C₁₋₆-alkyl)₂, —C₁₋₆-alkylene-NH(C₁₋₆-alkyl),    —C₁₋₆-alkylene-N(C₁₋₆-alkyl)₂, C₃₋₈-cycloalkyl, heterocyclyl, aryl,    heteroaryl, or a C₃₋₈-cycloalkyl, heterocyclyl, aryl or heteroaryl    group bonded via a C₁₋₆-alkylene group, C₂₋₆-alkenylene group or    C₂₋₆-alkynylene group;    wherein

said C₁₋₆-alkyl, C₁₋₆-alkylene, C₂₋₆-alkenylene, C₂₋₆-alkynylene,C₃₋₈-cycloalkyl, heterocyclyl, aryl and heteroaryl groups may beunsubstituted or mono- or poly-substituted with identical or differentsubstituents, and

said C₁₋₆-alkyl, C₁₋₆-alkylene, C₂₋₆-alkenylene, and C₂₋₆-alkynylenegroups may be branched or unbranched;

in the form of an individual enantiomer or an individual diastereomer,in the form of the racemate, enantiomers, diastereomers, mixtures of theenantiomers and/or diastereomers, as well as in each case in the form oftheir bases and/or physiologically compatible salts.

In the context of the present invention the term “halogen” preferablydenotes the groups F, Cl, Br and I, and particularly preferably thedenotes groups F, Cl and Br.

In the context of the present invention, the expression “C₁₋₆-alkyl”includes acyclic saturated hydrocarbon groups with 1, 2, 3, 4, 5 or 6carbon atoms, which may be branched or straight-chain (unbranched) aswell as unsubstituted or monosubstituted or polysubstituted, for example2, 3, 4 or 5 times, with identical or different substituents. Preferredalkyl groups are selected from the group consisting of methyl, ethyl,n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl,n-pentyl, iso-pentyl, neo-pentyl and hexyl. Particularly preferred alkylgroups are selected from the group consisting of methyl, ethyl,n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl and tert-butyl.

In the context of the present invention the expression “C₃₋₈-cycloalkyl”denotes cyclic saturated hydrocarbons with 3, 4, 5, 6, 7 or 8 carbonatoms, which may be unsubstituted or monosubstituted or polysubstitutedon one or more ring members, for example with 2, 3, 4 or 5 identical ordifferent substituents. Preferred C₃₋₈-cycloalkyl groups are selectedfrom the group consisting of cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl and cyclooctyl.

In the context of the present invention, the expression “heterocyclyl”denotes monocyclic or polycyclic, in particular mono-, bi- or tricyclicorganic groups, in which at least one cycle contains 1 heteroatom or 2,3, 4 or 5 identical or different heteroatoms, which is/are preferablyselected from the group consisting of N, O and S. Each heterocyclylgroup can be unsubstituted or monosubstituted or polysubstituted on oneor more ring members, for example with 2, 3, 4 or 5 identical ordifferent substituents. Saturated or unsaturated heterocyclyl areunderstood in particular to denote monocyclic 5-membered or 6-memberedgroups with at least one heteroatom selected from the group consistingof N, O and S, wherein a further 5-membered or 6-membered, saturated,unsaturated or aromatic cycle, which likewise can contain at least oneheteroatom selected from the group consisting of N, O and S, can becondensed onto these groups. Examples are the benzo-condensed orpyridino-condensed analogues of the aforementioned monocyclic 5- or6-membered compounds. Preferably a saturated or unsaturated heterocyclylgroup can be selected from the group consisting of azetidinyl,pyrrolidinyl, piperidinyl, piperazinyl, pyrazolinyl, morpholinyl,tetrahydropyranyl, dioxanyl, dioxolanyl, indolinyl, isoindolinyl and

Unless otherwise specified, the substitution with a heterocyclyl groupcan take place at any suitable position of the heterocyclyl group.

In the context of the present invention, the term “aryl” denotesaromatic hydrocarbons, in particular phenyl and naphthyl groups. Thearyl groups can also be condensed with further saturated, (partially)unsaturated or aromatic ring systems. Each aryl group can beunsubstituted or monosubstituted or polysubstituted, for example 2, 3, 4or 5 times, in which the aryl substituents can be identical or differentand can be in any arbitrary and possible position of the aryl.Preferably aryl can be selected from the group consisting of phenyl,1-naphthyl and 2-naphthyl, which can in each case be unsubstituted ormonosubstituted or polysubstituted, for example with 2, 3, 4 or 5groups.

In the context of the present invention, the term “heteroaryl” denotes a5-, 6- or 7-membered cyclic aromatic group, which contains at least 1,possibly also 2, 3, 4 or 5 heteroatoms, in which the heteroatoms can beidentical or different and the heteroaryl can be unsubstituted ormonosubstituted or polysubstituted, for example 2, 3, 4 or 5 times, withidentical or different substituents. The substituents can be bonded inany arbitrary and possible position of the heteroaryl. The heterocyclecan also be part of a bicyclic or polycyclic, in particular of amonocyclic, bicyclic or tricyclic system, which can then overall containmore than 7 members, preferably up to 14 members. Preferred heteroatomsare selected from the group consisting of N, O and S. The heteroarylgroup can preferably be selected from the group consisting of pyrrolyl,indolyl, furyl, (furanyl), benzofuranyl, thienyl (thiophenyl),benzothienyl, benzothiadiazolyl, benzothiazolyl, benzotriazolyl,benzodioxolanyl, benzodioxanyl, benzooxazolyl, benzooxadiazolyl,imidazothiazolyl, dibenzofuranyl, dibenzothienyl, phthalazinyl,pyrazolyl, imidazolyl, thiazolyl, oxadiazolyl, isoxazoyl, pyridinyl(pyridyl), pyridazinyl, pyrimidinyl, pyrazinyl, pyranyl, indazolyl,purinyl, indolizinyl, quinolinyl, isoquinolinyl, quinazolinyl,quinoxalinyl, carbazolyl, phenazinyl, phenothiazinyl and oxadiazolyl,wherein the bonding to the general structure I can take place via anyarbitrary and possible ring member of the heteroaryl group. Particularlypreferably the heteroaryl group can be selected from the groupconsisting of furyl, thienyl and pyridinyl.

In the context of the present invention, the expression “C₁₋₆-alkylenegroup” includes acyclic saturated hydrocarbon groups with 1, 2, 3, 4, 5or 6 C atoms, which can be branched or straight-chain (unbranched) aswell as unsubstituted or monosubstituted or polysubstituted, for example2, 3, 4 or 5 times, with identical or different substituents, and whichcouple a corresponding group to the overall general structure.Preferably the alkylene groups can be selected from the group consistingof —CH₂—, —CH₂—CH₂—, —CH(CH₃)—, —CH₂—CH₂—CH₂—, —CH(CH₃)—CH₂—,—CH(CH₂CH₃)—, —CH₂—(CH₂)₂—CH₂—, —CH(CH₃)—CH₂—CH₂—, —CH₂—CH(CH₃)—CH₂—,—CH(CH₃)—CH(CH₃), —CH(CH₂CH₃)—CH₂—, —C(CH₃)₂—CH₂, —CH(CH₂CH₂CH₃)—,—C(CH₃)(CH₂CH₃)—, —CH₂—(CH₂)₃—CH₂—, —CH(CH₃)—CH₂—CH₂—CH₂—,—CH₂—CH(CH₃)—CH₂—CH₂—, —CH(CH₃)—CH₂—CH(CH₃)—, —CH(CH₃)CH(CH₃)—CH₂—,—C(CH₃)₂—CH₂—CH₂—, —CH₂—C(CH₃)₂—CH₂—, —CH(CH₂CH₃)—CH₂—CH₂—,—CH₂—CH(CH₂CH₃)—CH₂—, —C(CH₃)₂—CH(CH₃)—, —CH(CH₂CH₃)—CH(CH₃)—,—C(CH₃)(CH₂CH₃)—CH₂—, —CH(CH₂CH₂CH₃)—CH₂—, —C(CH₂CH₂CH₃)—CH₂—,—CH(CH₂CH₂CH₂CH₃)—, —C(CH₃)(CH₂CH₂CH₃)—, —C(CH₂CH₃)₂— and—CH₂—(CH₂)₄—CH₂—. Particularly preferably the alkylene groups can beselected from the group consisting of —CH₂—, —CH₂—CH₂— and—CH₂—CH₂—CH₂—.

In the context of the present invention, the expression “C₂₋₆-alkenylenegroup” includes acyclic, monosubstituted or polysubstituted, for example2, 3 or 4 times, unsaturated hydrocarbon groups with 2, 3, 4, 5 or 6carbon atoms, which may be branched or straight-chain (unbranched) aswell as unsubstituted or monosubstituted or polysubstituted, for example2, 3, 4 or 5 times, with identical or different substituents, and whichcouple a corresponding group to the overall general structure. In thisconnection the alkenylene groups contain at least one C═C double bond.Preferably the alkenylene groups can be selected from the groupconsisting of —CH═CH—, —CH═CH—CH₂—, —C(CH₃)═CH₂—, —CH═CH—CH₂—CH₂—,—CH₂—CH═CH—CH₂—, —CH═CH—CH═CH—, —C(CH₃)═CH—CH₂—, —CH═C(CH₃)—CH₂—,—C(CH₃)═C(CH₃)—, —C(CH₂CH₃)═CH—, —CH═CH—CH₂—CH₂—CH₂—,—CH₂CH═CH₂—CH₂—CH₂—, —CH═CH═CH—CH₂—CH₂— and —CH═CH₂—CH—CH═CH₂—.

In the context of the present invention, the expression “C₂₋₆-alkynylenegroup” includes acyclic, monosubstituted or polysubstituted, for example2, 3 or 4 times, unsaturated hydrocarbon groups with 2, 3, 4, 5 or 6 Catoms, which may be branched or straight-chain (unbranched) as well asunsubstituted or monosubstituted or polysubstituted, for example 2, 3, 4or 5 times, with identical or different substituents, and which couple acorresponding group to the overall general structure. In this connectionthe alkynylene groups contain at least one C≡C triple bond. Preferablythe alkynylene groups can be selected from the group consisting of—C≡C—, —C≡C—CH₂—, —C≡C—CH₂—CH₂—, —C≡C—CH(CH₃)—, —CH₂—C≡C—CH₂—,—C≡C—C≡C—, —C≡C—C(CH₃)₂—, —C≡C—CH₂—CH₂CH₂—, —CH₂—C≡C—CH₂—CH₂—,—C≡C—C≡C—CH₂— and —C≡C—CH₂—C≡C—.

In the context of the present invention, the expression “aryl orheteroaryl group bonded via a C₁₋₆-alkylene group, C₂₋₆-alkenylene groupor C₂₋₆-alkynylene group” denotes that the C₁₋₆-alkylene groups,C₂₋₆-alkenylene groups or C₂₋₆-alkynylene groups as well as aryl and/orheteroaryl have the meanings given above and the aryl and/or heteroarylis/are bonded via a C₁₋₆-alkylene group, C₂₋₆-alkenylene group orC₂₋₆-alkynylene group to the overall general structure. Examples of suchgroups include benzyl, phenethyl and phenylpropyl groups.

In the context of the present invention, the expression “C₃₋₈-cycloalkyland heterocyclyl bonded via a C₁₋₆-alkylene group, C₂₋₆-alkenylene groupor C₂₋₆-alkynylene group” denotes that the C₁₋₆-alkylene group,C₂₋₆-alkenylene group, C₂₋₆-alkynylene group, C₃₋₈-cycloalkyl andheterocyclyl have the meanings given above and C₃₋₈-cycloalkyl andheterocyclyl are bonded via a C₁₋₆-alkylene group, C₂₋₆-alkenylene groupor C₂₋₆-alkynylene group to the overall general structure.

In the context of the present invention, the term “substituted” used inconnection with “alkyl”, “alkylene”, “alkenylene”, “alkynylene” and“cycloalkyl” is understood to denote the replacement of a hydrogen atomby F, Cl, Br, I, CN, NH₂, NH—C₁₋₆-alkyl, NH—C₁₋₆-alkylene-OH,C₁₋₆-alkyl, N(C₁₋₆-alkyl)₂, N(C₁₋₆-alkylene-OH)₂, NO₂, SH, S—C₁₋₆-alkyl,S-benzyl, O—C₁₋₆-alkyl, OH, O—C₁₋₆-alkylene-OH, ═O, O-benzyl,C(═O)C₁₋₆-alkyl, CO₂H, CO₂—C₁₋₆-alkyl, or benzyl, whereinpolysubstituted groups are understood to be those groups that aresubstituted several times, for example twice or three times, either ondifferent or on the same atoms, for example three times on the samecarbon atom as in the case of CF₃ or CH₂CF₃, or at different sites as inthe case of CH(Cl)—CH═CH—CHCl₂. The polysubstitution can be carried outwith identical or different substituents, as for example in the case ofCH(OH)—CH═CH—CHCl₂.

In connection with “heterocyclyl” the term “substituted” is understoodto denote the replacement of a hydrogen atom on one or more ring membersby F, Cl, Br, I, —CN, NH₂, NH—C₁₋₆-alkyl, NH—C₁₋₆-alkylene-OH,C₁₋₆-alkyl, N(C₁₋₆-alkyl)₂, N(C₁₋₆-alkylene-OH)₂, pyrrolinyl,piperazinyl, morpholinyl, NO₂, SH, S—C₁₋₆-alkyl, S-benzyl, O—C₁₋₆-alkyl,OH, O—C₁₋₆-alkylene-OH, ═O, O-benzyl, C(═O)C₁₋₆-alkyl, CO₂H,CO₂—C₁₋₆-alkyl or benzyl. The polysubstitution can be carried out withidentical or different substituents. In particular the hydrogen bondedto a N-heteroatom can be substituted by a C₁₋₆-alkyl group.

With regard to “aryl” and “heteroaryl”, in the context of the presentinvention, the term “substituted” is understood to denotemonosubstitution or polysubstitution, for example 2, 3, 4 or 5 times, ofone or more hydrogen atoms of the corresponding ring system by F, Cl,Br, I, CN, NH₂, NH—C₁₋₆-alkyl, NH—C₁₋₆-alkylene-OH, N(C₁₋₆-alkyl)₂,N(C₁₋₆-alkylene-OH)₂, NH-aryl¹, N(aryl¹)₂, N(C₁₋₆-alkyl)aryl¹,pyrrolinyl, piperazinyl, morpholinyl, NO₂, SH, S—C₁₋₆-alkyl, OH,O—C₁₋₆-alkyl, O—C₁₋₆-alkyl-OH, C(═O)C₁₋₆-alkyl, NHSO₂C₁₋₆-alkyl,NHCOC₁₋₆-alkyl, CO₂H, CH₂SO₂-phenyl, CO₂—C₁₋₆-alkyl, OCF₃, CF₃,—O—CH₂—O—, —O—CH₂—CH₂—O—, —O—C(CH₃)₂—CH₂—, unsubstituted C₁₋₆-alkyl,pyrrolidinyl, imidazolyl, piperidinyl, benzyloxy, phenoxy, phenyl,naphthyl, pyridinyl, —C₁₋₃-alkylene-aryl¹, benzyl, thienyl, furyl,wherein aryl¹ denotes phenyl, furyl, thienyl or pyridinyl, on one orvarious atoms, wherein the aforementioned substituents—unless otherwisespecified—may optionally for their part be substituted by theaforementioned substituents. The polysubstitution of aryl and heteroarylcan take place with identical or different substituents. Preferredsubstituents for aryl and heteroaryl can be selected from the groupconsisting of —O—C₁₋₃-alkyl, C₁₋₆-alkyl, F, Cl, Br, I, CF₃, OCF₃, OH,SH, phenyl, naphthyl, furyl, thienyl and pyridinyl, in particular fromthe group consisting of F, Cl, Br, CF₃, CH₃ and OCH₃.

In the context of the present invention the symbol

used in the formulas denotes a coupling of a corresponding group to therespective overall general structure.

In the context of the present invention, the expression “physiologicallycompatible salt” is to be understood to denote salts of the compoundsaccording to the invention with inorganic or organic acids that arephysiologically compatible, especially when used in humans and/ormammals. Examples of suitable acids include hydrochloric acid,hydrobromic acid, sulfuric acid, methanesulfonic acid, formic acid,acetic acid, oxalic acid, succinic acid, tartaric acid, mandelic acid,fumaric acid, maleic acid, lactic acid, citric acid, glutamic acid,1,1-dioxo-1,2-dihydroλ⁶-benzo[d]isothiazol-3-one (saccharinic acid),monomethylsebacic acid, 5-oxoproline, hexane-1-sulfonic acid, nicotinicacid, 2-, 3- or 4-aminobenzoic acid, 2,4,6-trimethylbenzoic acid,α-lipoic acid, acetylglycine, hippuric acid, phosphoric acid and/oraspartic acid. Particularly preferred are the salts of hydrochloric acid(hydrochlorides) as well as of citric acid (citrates).

In one preferred embodiment of the present invention, the group R¹ inthe substituted sulfonamide compounds according to the invention denotesphenyl, naphthyl, indolyl, benzofuranyl, benzothiophenyl (benzothienyl);benzooxazolyl, benzooxadiazolyl, pyrrolyl, furanyl, thienyl, pyridinyl,pyridazinyl, pyrimidinyl, pyrazinyl, imidazothiazolyl, carbazolyl,dibenzofuranyl or dibenzothiophenyl (dibenzothienyl), preferably denotesphenyl, naphthyl, benzothiophenyl, benzooxadiazolyl, thiophenyl,pyridinyl, imidazothiazolyl or dibenzofuranyl, and particularlypreferably denotes phenyl or naphthyl, in each case unsubstituted ormonosubstituted or polysubstituted with identical or differentsubstituents, wherein the substituents are preferably selected from thegroup consisting of —O—C₁₋₃-alkyl, C₁₋₆-alkyl, F, Cl, Br, I CF₃, OCF₃,OH, SH, phenyl, naphthyl, furyl, thienyl and pyridinyl.

In another preferred embodiment of the present invention, the group R¹in the substituted sulfonamide compounds according to the inventiondenotes phenyl or naphthyl, wherein the phenyl or naphthyl may beunsubstituted or monosubstituted or polysubstituted, for example 2, 3, 4or 5 times, with identical or different substituents selected from thegroup consisting of methyl, methoxy, CF₃, OCF₃, F, Cl and Br.

In still another preferred embodiment, the group R¹ in the sulfonamidecompounds according to the invention is selected from the groupconsisting of 4-methoxy-2,3,6-trimethylphenyl,4-methoxy-2,6-dimethylphenyl, 4-methoxy2,3,5-trimethylphenyl,2,4,6-trimethylphenyl, 2-chloro-6-methylphenyl, 2,4,6-trichlorophenyl,2-chloro-6-(trifluoromethyl)phenyl, 2,6-dichloro-4-methoxyphenyl,2-methylnaphthyl, 2-chloronaphthyl, 2-fluoronaphthyl,2-chloro-4-(trifluoromethoxy)phenyl, 4-chloro-2,5-dimethylphenyl,2,3-dichlorophenyl, 3,4-dichlorophenyl, 2(trifluoromethyl)phenyl,3-(trifluoromethyl)phenyl, 4-(trifluoromethyl)phenyl, 1-naphthyl and2-naphthyl.

In yet another preferred embodiment the group R¹ in the sulfonamidecompounds according to the invention is selected from the groupconsisting of 4-methoxy-2,3,6-trimethylphenyl,4-methoxy-2,6-dimethylphenyl, 4-methoxy2,3,5-trimethylphenyl,2,4,6-trimethylphenyl, 4-chloro-2,5-dimethylphenyl, 2,3-dichlorophenyl,3,4-dichlorophenyl, 2-(trifluoromethyl)phenyl,3-(trifluoromethyl)phenyl, 4-(trifluoromethyl)phenyl, 1-naphthyl and2-naphthyl.

In another preferred embodiment, the group R¹ in the sulfonamidecompounds according to the invention is selected from the groupconsisting of 4-methoxy-2,3,6-trimethylphenyl,4-methoxy-2,6-dimethylphenyl, 4-methoxy-2,3,5-trimethylphenyl,2,4,6-trimethylphenyl, 1-naphthyl and 2-naphthyl.

Preferably R² in the sulfonamide compounds according to the inventiondenotes H, C₁₋₆-alkyl or aryl; or denotes an aryl bonded via aC₁₋₆-alkylene group, C₂₋₆-alkenylene group or C₂₋₆-alkynylene group,wherein the aryl may be unsubstituted or monosubstituted orpolysubstituted with identical or different substituents selected fromthe group consisting of C₁₋₆-alkyl, C₁₋₆-alkyl-O—, F, Cl, Br, I CF₃,OCF₃, OH and SH.

In a further preferred embodiment of the sulfonamide compounds accordingto the invention, R² denotes H, C₁₋₆-alkyl or phenyl; or denotes aphenyl bonded via a C₁₋₆-alkylene group, wherein the phenyl may beunsubstituted or monosubstituted or polysubstituted with identical ordifferent substituents selected from the group consisting of methyl,ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl,methoxy, F, Cl, Br, I, CF₃, OCF₃ and OH.

In a further preferred embodiment of the sulfonamide compounds accordingto the invention, R² denotes H, methyl, ethyl, n-propyl, iso-propyl,n-butyl, iso-butyl, sec-butyl, tert-butyl, benzyl or phenethyl.

Preferably R³ in the sulfonamide compounds according to the inventioncan denote H, C₁₋₆-alkyl or aryl; or can denote an aryl bonded via aC₁₋₆-alkylene group, C₂₋₆-alkenylene group or C₂₋₆-alkynylene group, thearyl in each case being unsubstituted or monosubstituted orpolysubstituted with identical or different substituents selected fromthe group consisting of C₁₋₆-alkyl, C₁₋₆-alkyl-O—, F, Cl, Br, I, CF₃,OCF₃, OH and SH.

In a further preferred embodiment of the sulfonamide compounds accordingto the invention, R³ denotes H or phenyl, wherein the phenyl may beunsubstituted or monosubstituted or polysubstituted with identical ordifferent substituents selected from the group consisting of methyl,ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl,methoxy, F, Cl, Br, I, CF₃, OCF₃ and OH.

In another preferred embodiment of the sulfonamide compounds accordingto the invention, R³ denotes H or unsubstituted phenyl.

In yet another preferred embodiment of the sulfonamide compoundsaccording to the invention:

-   -   if Q=—O—, then m and n are each equal to 1, and    -   if Q=—CH₂—, then the sum of m+n=0 or 1.

In a further preferred embodiment of the sulfonamide compounds accordingto the invention:

-   -   if Q=—O—, then m and n each equal 1, and    -   if Q=—CH₂—, then the sum of m+n=0.

In still another preferred embodiment of the substituted sulfonamidecompounds according to the invention, p denotes 1.

In a further preferred embodiment of the sulfonamide compounds accordingto the invention, R⁴ denotes H, C₁₋₆-alkyl, aryl, heteroaryl, or an arylor heteroaryl group bonded via a C₁₋₆-alkylene group, C₂₋₆-alkenylenegroup or C₂₋₆-alkynylene group, wherein the aryl or heteroarylpreferably is selected from the group consisting of phenyl, naphthyl,pyridinyl, thienyl and furyl, and wherein the aryl or heteroaryl may beunsubstituted or monosubstituted or polysubstituted by identical ordifferent substituents selected from the group consisting ofO—C₁₋₃-alkyl, unsubstituted C₁₋₆-alkyl, F, Cl, Br, I, CF₃, OCF₃, OH andSH.

In a further preferred embodiment of the sulfonamide compounds accordingto the invention R⁴ denotes H, C₁₋₆-alkyl, phenyl, furyl, thienyl,pyridinyl, or a phenyl, furyl, thienyl or pyridinyl group bonded via aC₁₋₃-alkylene group, wherein the phenyl, furyl, thienyl or pyridinyl maybe unsubstituted or monosubstituted or polysubstituted by identical ordifferent substituents selected from the group consisting of—O—C₁₋₃-alkyl, unsubstituted C₁₋₆-alkyl, F, Cl, Br, I, CF₃, OCF₃, OH,SH.

In yet another preferred embodiment of the sulfonamide compoundsaccording to the invention, R⁴ denotes a group selected from the groupconsisting of H, methyl, ethyl, n-propyl, iso-propyl, n-butyl,sec-butyl, iso-butyl, tert-butyl, phenyl, 2,3-dimethylphenyl,3,4-dimethylphenyl, 2-tert-butylphenyl, 3-tert-butylphenyl,4-tert-butylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl,2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,3-difluorophenyl,3,4-difluorophenyl, 2(trifluoromethyl)phenyl, 3-(trifluoromethyl)phenyl,4-(trifluoromethyl)phenyl, 2-fluoro-4(trifluoromethyl)phenyl,3-fluoro-4-(trifluoromethyl)phenyl, benzyl, phenethyl, thienyl, pyridyland 6-chloro-pyridin-3-yl.

In still another preferred embodiment of the present invention, X in thesubstituted sulfonamide compounds according to the invention denotes N;Y denotes CR⁶, and Z denotes CR⁷.

In a further embodiment of the present invention, in the substitutedsulfonamide compounds according to the invention X denotes N, Y denotesN, and Z denotes CR⁷.

In a further embodiment of the present invention, in the substitutedsulfonamide compounds according to the invention X denotes CR⁵, Ydenotes CR⁶ and Z denotes CR⁷.

In a still further preferred embodiment of the sulfonamide compoundsaccording to the invention, R⁵, R⁶ and R⁷ each independently denote H,halogen, C₁₋₆-alkyl, —N(C₁₋₆-alkyl)₂, —C₁₋₆-alkylene-N(C₁₋₆-Alkyl)₂, a5-, 6- or 7-membered heterocyclyl, 5- or 6-membered heteroaryl, a 5- or6-membered heteroaryl, or a 5-, 6- or 7-membered heterocyclyl bonded viaa C₁₋₆-alkylene group, wherein heterocyclyl comprises one or twoidentical or different heteroatoms selected from the group consisting ofN and O, and may be unsubstituted or monosubstituted or identically ordifferently polysubstituted with C₁₋₆-alkyl.

In a further preferred embodiment of the sulfonamide compounds accordingto the invention, R⁵, R⁶ and R⁷ each independently denote H, F, Cl, Br,I, C₁₋₆-alkyl, or a group selected from the group consisting of:

wherein

-   R⁸ and R⁹ each independently denote a C₁₋₆-alkyl group;-   j is 1, 2 or 3;-   R¹⁰ denotes a group selected from the group consisting of H, methyl,    ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl,    tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; and-   M¹, M² und M³ each independently denote N or CH, wherein one of M¹,    M² and M³ represents N, and the other two of M¹, M² and M³ each    represent CH.

Preferably R⁵ in the compounds according to the invention denotes H.

In a further preferred embodiment of the compounds according to theinvention R⁶ denotes H or a group selected from the group consisting of

wherein

-   R⁸ and R⁹ each independently denote a C₁₋₆-alkyl group;-   j is 1, 2 or 3; and-   M¹, M² und M³ each independently denote N or CH, wherein one of M¹,    M² and M³ represents N, and the other two of M¹, M² and M³ each    represent CH.

In another preferred embodiment of the compounds according to theinvention, R⁷ denotes H, F, Cl, Br, I, C₁₋₆-alkyl, or a group selectedfrom the group consisting of:

wherein

-   R⁸ and R⁹ each independently denote a C₁₋₆-alkyl group,-   j is 1, 2 or 3; and-   M¹, M² und M³ each independently denote N or CH, wherein one of M¹,    M² and M³ represents N, and the other two of M¹, M² and M³ each    represent CH.

Also preferred are substituted sulfonamide compounds of the inventionwherein: m and n each independently denote 0 or 1;

-   p is 1;-   Q denotes —O— or —CH₂;-   X denotes N or CR⁵;-   Y denotes N or CR⁶;-   Z denotes N or CR⁷;-   R¹ denotes phenyl, naphthyl, indolyl, benzofuranyl, benzothiophenyl    (benzothienyl); benzooxazolyl, benzooxadiazolyl, pyrrolyl, furanyl,    thienyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl,    imidazothiazolyl, carbazolyl, dibenzofuranyl or dibenzothiophenyl    (dibenzothienyl), preferably phenyl, naphthyl, benzothiophenyl,    benzooxadiazolyl, thiophenyl, pyridinyl, imidazothiazolyl or    dibenzofuranyl, and particularly preferably denotes phenyl or    naphthyl, in each case unsubstituted or monosubstituted or    polysubstituted with identical or different substituents, wherein    the substituents are preferably selected from the group consisting    of —O—C₁₋₃-alkyl, C₁₋₆-alkyl, F, Cl, Br, I CF₃, OCF₃, OH, SH,    phenyl, naphthyl, furyl, thienyl and pyridinyl;-   R² denotes H, C₁₋₆-alkyl, aryl, or an aryl group bonded via a    C₁₋₆-alkylene group, C₂₋₆-alkenylene group or C₂₋₆-alkynylene group,    wherein the aryl may be unsubstituted or monosubstituted or    polysubstituted with identical or different substituents selected    from the group consisting of C₁₋₆-alkyl, C₁₋₆-alkyl-O—, F, Cl, Br,    I, CF₃, OCF₃, OH, and SH;-   R³ denotes H, C₁₋₆-alkyl, aryl, or an aryl group bonded via a    C₁₋₆-alkylene group, C₂₋₆-alkenylene group or C₂₋₆-alkynylene group,    which aryl may be unsubstituted or monosubstituted or    polysubstituted with identical or different substituents selected    from the group consisting of C₁₋₆-alkyl, C₁₋₆-alkyl-O—, F, Cl, Br,    I, CF₃, OCF₃, OH and SH;-   R⁴ denotes H, C₁₋₆-alkyl, aryl, heteroaryl, or an aryl or heteroaryl    group bonded via a C₁₋₆-alkylene group, C₂₋₆-alkenylene group or    C₂₋₆-alkynylene group, wherein the aryl or heteroaryl is preferably    selected from the group consisting of phenyl, naphthyl, pyridinyl,    thienyl and furyl, and may be unsubstituted or monosubstituted or    polysubstituted with identical or different substituents selected    from the group consisting of O—C₁₋₃-alkyl, unsubstituted C₁₋₆-alkyl,    F, Cl, Br, I, CF₃, OCF₃, OH and SH.-   R⁵, R⁶ and R⁷ each independently denote H, halogen, C₁₋₆-alkyl,    —N(C₁₋₆-alkyl)₂, —C₁₋₆-alkylene-N(C₁₋₆-alkyl)₂, 5- or 6-membered    heterocyclyl, 5- or 6-membered heteroaryl, or a 5- or 6-membered    heteroaryl or 5- or 6-membered heterocyclyl group bonded via a    C₁₋₆-alkylene group, wherein heterocyclyl comprises 1 or 2 identical    or different heteroatoms selected from the group consisting of N and    O and may be unsubstituted or is monosubstituted or identically or    differently polysubstituted with C₁₋₆-alkyl;    in the form of an individual enantiomer or an individual    diastereomer, in the form of the racemate, enantiomers,    diastereomers, mixtures of the enantiomers and/or diastereomers, as    well as in the form of their bases and/or physiologically compatible    salts.

In addition substituted sulfonamide compounds according to the inventionare preferred in which

if Q=—O—, then m and j are each 1, andif Q=—CH₂—, then the sum of m+n=0 or 1;

-   p is 1;-   R¹ denotes phenyl or naphthyl, which may be unsubstituted or    monosubstituted or identically or differently polysubstituted with    substituents selected from the group consisting of methyl, methoxy,    CF₃, F, Cl and Br;-   R² denotes H, C₁₋₆-alkyl, phenyl, or a phenyl group bonded via a    C₁₋₆-alkylene group, wherein the phenyl may be unsubstituted or    monosubstituted or polysubstituted with identical or different    substituents selected from the group consisting of methyl, ethyl,    n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl,    methoxy, F, Cl, Br, I, CF₃, OCF₃ and OH;-   R³ denotes H or phenyl, which phenyl may be unsubstituted or    monosubstituted or polysubstituted with identical or different    substituents selected from the group consisting of methyl, ethyl,    n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl,    methoxy, F, Cl, Br, I, CF₃, OCF₃ and OH;-   R⁴ denotes H, C₁₋₆-alkyl, phenyl, furyl, thienyl or pyridinyl; or    denotes a phenyl, furyl, thienyl or pyridinyl bonded via a    C₁₋₃-alkylene group, wherein the phenyl, furyl, thienyl or pyridinyl    are in each case unsubstituted or monosubstituted or identically or    differently polysubstituted, the substituents being selected from    the group consisting of —O—C₁₋₃-alkyl, unsubstituted C₁₋₆-alkyl, F,    Cl, Br, I, CF₃, OCF₃, OH, SH;-   R⁵ denotes H;-   R⁶ denotes H or a group selected from the group consisting of:

wherein

-   -   R⁸ and R⁹ each independently denote a C₁₋₆-alkyl group;    -   j is 1, 2 or 3; and    -   M¹, M² und M³ each independently denote N or CH, wherein one of        M¹, M² and M³ represents N, and the other two of M¹, M² and M³        each represent CH;        R⁷ denotes H, F, Cl, Br, I, C₁₋₆-alkyl, or a group selected from        the group consisting of

wherein

-   -   R⁸ and R⁹ each independently denote a C₁₋₆-alkyl group;    -   j is 1, 2 or 3; and    -   M¹, M² und M³ each independently denote N or CH, wherein one of        M¹, M² and M³ represents N, and the other two of M¹, M² and M³        each represent CH.

According to a further embodiment of the present invention substitutedsulfonamide compounds are preferred in which

m=1, n=1, and Q denotes —O—; orm=1, n=0, and Q denotes —CH₂—; orm=0, n=1, and Q denotes —CH₂—; orm=0, n=0 and Q denotes —CH₂—;

-   p denotes 1;-   X denotes N or CR⁵;-   Y denotes N or CR⁶;-   Z denotes N or CR⁷;-   R¹ denotes phenyl or naphthyl, which may be unsubstituted or    monosubstituted or identically or differently disubstituted,    trisubstituted, quadruply substituted or pentasubstituted with    substituents selected from the group consisting of methyl, methoxy,    CF₃, F, Cl and Br;-   R² denotes H, methyl, ethyl, n-propyl, iso-propyl, n-butyl,    iso-butyl, sec-butyl, tert-butyl, phenyl, or a phenyl group bonded    via a —CH₂—, —(CH₂)₂— or —(CH₂)₃— group, wherein the phenyl may be    unsubstituted or monosubstituted or disubstituted, trisubstituted,    tetrasubstituted or pentasubstituted with identical or different    substituents selected from the group consisting of methyl, ethyl,    n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl,    methoxy, F, Cl, Br, I, CF₃, OCF₃ and OH;-   R³ denotes H or unsubstituted phenyl,-   R⁴ denotes H, methyl, ethyl, n-propyl, iso-propyl, n-butyl,    iso-butyl, sec-butyl, tert-butyl, phenyl, furyl, thienyl, pyridinyl,    or a phenyl, furyl, thienyl or pyridinyl group bonded via a —(CH₂)—,    —(CH₂)₂— or —(CH₂)₃— group, wherein the phenyl, furyl, thienyl or    pyridinyl may be unsubstituted or monosubstituted, disubstituted or    trisubstituted with substituents independently selected from the    group consisting of methoxy, ethoxy, n-propoxy, iso-propoxy, methyl,    ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl,    tert-butyl, F, Cl, Br, I, CF₃, OCF₃, OH and SH;-   R⁵ denotes H;-   R⁶ denotes H or a group selected from the group consisting of

wherein

-   -   R⁸ and R⁹ each denote a methyl group;    -   j is 1, 2 or 3; and    -   M¹, M² und M³ each independently denote N or CH, wherein one of        M¹, M² and M³ represents N, and the other two of M¹, M² and M³        each represent CH;

-   R⁷ denotes H, F, Cl, Br, I, methyl, ethyl, n-propyl, iso-propyl,    n-butyl, iso-butyl, sec-butyl, tert-butyl, or a group selected from    the group consisting of

wherein

-   -   R⁸ and R⁹ each denote a methyl group;    -   j is 1, 2 or 3; and    -   M¹, M² und M³ each independently denote N or CH, wherein one of        M¹, M² and M³ represents N, and the other two of M¹, M² and M³        each represent CH.

Also preferred are sulfonamide compounds according to the inventioncorresponding to formula Ib

wherein

-   X denotes N or CR⁵;-   Y denotes N or CR⁶;-   Z denotes N or CR⁷;-   R⁴ denotes H, methyl, ethyl, n-propyl, iso-propyl, n-butyl,    iso-butyl, sec-butyl, tert-butyl, phenyl, furyl, thienyl, pyridinyl,    or a phenyl group bonded via a —(CH₂)—, —(CH₂)₂— or —(CH₂)₃— group,    wherein the phenyl, furyl, thienyl or pyridinyl may be unsubstituted    or monosubstituted or identically or differently disubstituted or    trisubstituted with substituents independently selected from the    group consisting of methoxy, ethoxy, n-propoxy, iso-propoxy, methyl,    ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, F, Cl,    Br, I CF₃, OCF₃, OH and SH;-   R⁵ denotes H;-   R⁶ denotes H or a group selected from the group consisting of

wherein

-   -   R⁸ and R⁹ each independently denote a methyl group;    -   j is 1, 2 or 3; and    -   M¹, M² und M³ each independently denote N or CH, wherein one of        M¹, M² and M³ represents Nn and the other two of M¹, M² and M³        each represent CH;

-   R⁷ denotes H, F, Cl, Br, I, methyl, ethyl, n-propyl, iso-propyl,    n-butyl, iso-butyl, sec-butyl, tert-butyl, or a group selected from    the group consisting of:

wherein

-   -   R⁸ and R⁹ each independently denote a methyl group;    -   j is 1, 2 or 3; and    -   M¹, M² und M³ each independently denote N or CH, wherein one of        M¹, M² and M³ represents N, and the other two of M¹, M² and M³        each represent CH.

According to a further preferred embodiment of the invention, thesulfonamide compounds according to the invention are selected from thegroup consisting of:

-   (1)    N-(2-(2-(6-((dimethylamino)methyl)-1-phenyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,3,6-tetramethylbenzene-sulfonamide,-   (2)    4-methoxy-N,2,6-trimethyl-N-(2-(2-oxo-2-(2-(piperidin-1-ylmethyl)-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)ethoxy)ethyl)benzenesulfonamide,-   (3)    N-(2-(2-(5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,6-trimethylbenzenesulfonamide,-   (4)    (R)—N-(3-oxo-1-phenyl-3-(2-(piperidin-1-ylmethyl)-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)propyl)naphthalene-2-sulfonamide,-   (5)    (R)—N-(3-(3-chloro-2-(piperidin-1-ylmethyl)-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)-3-oxo-1-phenylpropyl)naphthalene-2-sulfonamide,-   (6)    N-(2-(2-(3-chloro-2-(piperidin-1-ylmethyl)-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,6-trimethylbenzenesulfonamide,-   (7)    4-methoxy-N,2,6-trimethyl-N-(2-(2-(6-(morpholinomethyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)benzenesulfonamide,-   (8)    N-(3-oxo-1-phenyl-3-(6-(pyrrolidin-1-ylmethyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)propyl)naphthalene-2-sulfonamide,-   (9)    4-methoxy-N,2,6-trimethyl-N-(2-(2-(6-((4-methylpiperazin-1-yl)methyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)benzenesulfonamide,-   (10)    N-(3-(6-(morpholinomethyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-3-oxo-1-phenylpropyl)naphthalene-2-sulfonamide,-   (11)    4-methoxy-N,2,6-trimethyl-N-(2-(2-oxo-2-(6-(pyrrolidin-1-ylmethyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide,-   (12)    4-methoxy-N,2,6-trimethyl-N-(2-(2-(6-(3-(4-methylpiperazin-1-yl)propyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)benzenesulfonamide,-   (13)    N-(3-(6-(3-(4-methylpiperazin-1-yl)propyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-3-oxo-1-phenylpropyl)naphthalene-2-sulfonamide,-   (14)    N-(2-(2-(6-((dimethylamino)methyl)-1-phenyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,6-trimethylbenzenesulfonamide,-   (15)    4-methoxy-N,2,6-trimethyl-N-(2-(2-oxo-2-(1-phenyl-6-(pyrrolidin-1-ylmethyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide,-   (16)    4-methoxy-N,2,6-trimethyl-N-(2-(2-oxo-2-(1-phenyl-6-(piperidin-1-ylmethyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide,-   (17)    N-(2-(2-(6-((dimethylamino)methyl)-1-(thiophen-2-yl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,6-trimethylbenzene-sulfonamide,-   (18)    N-(2-(2-(1-tert-butyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-N-isobutyl-4-methoxy-2,3,6-trimethylbenzenesulfonamide,-   (19)    N-isobutyl-4-methoxy-2,3,6-trimethyl-N-(2-(2-oxo-2-(1-(pyridin-3-yl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide,-   (20)    N-(2-(2-(1-(6-chloropyridin-3-yl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-N-isobutyl-4-methoxy-2,3,6-trimethylbenzenesulfonamide,-   (21)    N-(2-(2-(5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)-2-oxoethoxy)ethyl)-N-isobutyl-4-methoxy-2,3,6-trimethylbenzenesulfonamide,-   (22)    N-isobutyl-4-methoxy-N-(2-(2-(1-(4-methoxyphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-2,3,6-trimethylbenzenesulfonamide,-   (23)    N-isobutyl-4-methoxy-2,3,6-trimethyl-N-(2-(2-oxo-2-(1-phenyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide,-   (24)    N-(2-(2-(1-(3-fluorophenyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-N-isobutyl-4-methoxy-2,3,6-trimethylbenzenesulfonamide,-   (25)    N-isobutyl-4-methoxy-2,3,6-trimethyl-N-(2-(2-oxo-2-(1-(thiophen-2-yl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide,-   (26)    N-isobutyl-4-methoxy-N-(2-(2-(1-(3-methoxyphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-2,3,6-trimethylbenzenesulfonamide,-   (27)    N-(2-(2-(1-tert-butyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,3,5-tetramethylbenzenesulfonamide,-   (28)    4-methoxy-N,2,3,5-tetramethyl-N-(2-(2-(1-methyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)benzenesulfonamide,-   (29)    4-methoxy-N,2,3,5-tetramethyl-N-(2-(2-oxo-2-(1-(pyridin-3-yl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide,-   (30)    N-(2-(2-(1-(6-chloropyridin-3-yl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,3,5-tetramethylbenzenesulfonamide,-   (31)    4-methoxy-N-(2-(2-(1-(4-methoxyphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-N,2,3,5-tetramethylbenzenesulfonamide,-   (32)    4-methoxy-N,2,3,5-tetramethyl-N-(2-(2-oxo-2-(1-phenyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide,-   (33)    N-(2-(2-(1-(3,4-difluorophenyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,3,5-tetramethylbenzenesulfonamide,-   (34)    N-(2-(2-(1-(3,4-dimethylphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,3,5-tetramethylbenzenesulfonamide,-   (35)    N-(2-(2-(1-(3-fluorophenyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,3,5-tetramethylbenzenesulfonamide,-   (36)    4-methoxy-N,2,3,5-tetramethyl-N-(2-(2-oxo-2-(1-(thiophen-2-yl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide,-   (37)    4-methoxy-N,2,3,5-tetramethyl-N-(2-(2-oxo-2-(1-(3-(trifluoromethyl)phenyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide,-   (38)    4-methoxy-N-(2-(2-(1-(3-methoxyphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-N,2,3,5-tetramethylbenzenesulfonamide,-   (39)    N-(2-(2-(1-(2-fluoro-4-(trifluoromethyl)phenyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,3,5-tetramethyl-benzenesulfonamide,-   (40)    N-benzyl-4-methoxy-2,3,6-trimethyl-N-(2-(2-(1-methyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)benzenesulfonamide,-   (41)    N-benzyl-4-methoxy-2,3,6-trimethyl-N-(2-(2-oxo-2-(1-(pyridin-3-yl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide,-   (42)    N-benzyl-N-(2-(2-(1-(6-chloropyridin-3-yl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-2,3,6-trimethylbenzenesulfonamide,-   (43)    N-benzyl-N-(2-(2-(5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-2,3,6-trimethylbenzenesulfonamide,-   (44)    N-benzyl-N-(2-(2-(1-tert-butyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-2,6-dimethylbenzenesulfonamide,-   (45)    N-benzyl-4-methoxy-2,6-dimethyl-N-(2-(2-(1-methyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)benzenesulfonamide,-   (46)    N-benzyl-N-(2-(2-(5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-2,6-dimethylbenzenesulfonamide,-   (47)    N-benzyl-4-methoxy-N-(2-(2-(1-(4-methoxyphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-2,6-dimethylbenzenesulfonamide,-   (48)    N-benzyl-4-methoxy-2,6-dimethyl-N-(2-(2-oxo-2-(1-phenyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide,-   (49)    N-benzyl-N-(2-(2-(1-(3,4-dimethylphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-2,6-dimethylbenzenesulfonamide,-   (50)    N-benzyl-4-methoxy-2,6-dimethyl-N-(2-(2-oxo-2-(1-(thiophen-2-yl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide,-   (51)    N-benzyl-N-(2-(2-(1-(4-tert-butylphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-2,6-dimethylbenzenesulfonamide,-   (52)    N-(2-(2-(1-tert-butyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,6-trimethylbenzenesulfonamide,-   (53)    4-methoxy-N,2,6-trimethyl-N-(2-(2-(1-methyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)benzenesulfonamide,-   (54)    4-methoxy-N,2,6-trimethyl-N-(2-(2-oxo-2-(1-(pyridin-3-yl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide,-   (55)    N-(2-(2-(1-(6-chloropyridin-3-yl)-3,4-dihydropyrrolo-[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,6-trimethylbenzenesulfonamide,-   (56)    N-(2-(2-(5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,6-trimethylbenzenesulfonamide,-   (57)    N-(2-(2-(1-(3,4-difluorophenyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,6-trimethylbenzenesulfonamide,-   (58)    N-(2-(2-(1-(3,4-dimethylphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,6-trimethylbenzenesulfonamide,-   (59)    N-(2-(2-(1-(3-fluorophenyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,6-trimethylbenzenesulfonamide,-   (60)    4-Methoxy-N,2,6-trimethyl-N-(2-(2-oxo-2-(1-(thiophen-2-yl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide,-   (61)    4-methoxy-N,2,6-trimethyl-N-(2-(2-oxo-2-(1-(3-(trifluoromethyl)phenyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide,-   (62)    4-methoxy-N-(2-(2-(1-(3-methoxyphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-N,2,6-trimethylbenzenesulfonamide,-   (63)    N-(2-(2-(1-(2-fluoro-4-(trifluoromethyl)phenyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,6-trimethylbenzene-sulfonamide,-   (64)    N-(2-(2-(1-(4-tert-butylphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,6-trimethylbenzenesulfonamide,-   (65)    N-(2-(2-(1-tert-butyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-N,2,4,6-tetramethylbenzenesulfonamide,-   (66)    N,2,4,6-tetramethyl-N-(2-(2-(1-methyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)benzenesulfonamide,-   (67)    N,2,4,6-tetramethyl-N-(2-(2-oxo-2-(1-(pyridin-3-yl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide,-   (68)    N-(2-(2-(1-(6-chloropyridin-3-yl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-N,2,4,6-tetramethylbenzenesulfonamide,-   (69)    N-(2-(2-(1-(4-methoxyphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-N,2,4,6-tetramethylbenzenesulfonamide,-   (70)    N,2,4,6-tetramethyl-N-(2-(2-oxo-2-(1-phenyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide,-   (71)    N-(2-(2-(1-(3,4-difluorophenyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-N,2,4,6-tetramethylbenzenesulfonamide,-   (72)    N-(2-(2-(1-(3,4-dimethylphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-N,2,4,6-tetramethylbenzenesulfonamide,-   (73)    N-(2-(2-(1-(3-fluorophenyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-N,2,4,6-tetramethylbenzenesulfonamide,-   (74)    N,2,4,6-tetramethyl-N-(2-(2-oxo-2-(1-(thiophen-2-yl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide,-   (75)    N,2,4,6-tetramethyl-N-(2-(2-oxo-2-(1-(3-(trifluoromethyl)phenyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide,-   (76)    N-(2-(2-(1-(3-methoxyphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-N,2,4,6-tetramethylbenzenesulfonamide,-   (77)    N-(2-(2-(1-(2-fluoro-4-(trifluoromethyl)phenyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-N,2,4,6-tetramethylbenzenesulfonamide,-   (78)    N-(2-(2-(1-(4-tert-butylphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-N,2,4,6-tetramethylbenzenesulfonamide,-   (79)    N-(2-(2-(1-tert-butyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,3,6-tetramethylbenzenesulfonamide,-   (80)    4-methoxy-N,2,3,6-tetramethyl-N-(2-(2-(1-methyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)benzenesulfonamide,-   (81)    4-methoxy-N,2,3,6-tetramethyl-N-(2-(2-oxo-2-(1-(pyridin-3-yl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide,-   (82)    N-(2-(2-(1-(6-chloropyridin-3-yl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,3,6-tetramethylbenzenesulfonamide,-   (83)    4-methoxy-N-(2-(2-(1-(4-methoxyphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-N,2,3,6-tetramethylbenzenesulfonamide,-   (84)    4-methoxy-N,2,3,6-tetramethyl-N-(2-(2-oxo-2-(1-phenyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide,-   (85)    N-(2-(2-(1-(3,4-difluorophenyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,3,6-tetramethylbenzenesulfonamide,-   (86)    N-(2-(2-(1-(3,4-dimethylphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,3,6-tetramethylbenzenesulfonamide,-   (87)    N-(2-(2-(1-(3-fluorophenyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,3,6-tetramethylbenzenesulfonamide,-   (88)    4-methoxy-N,2,3,6-tetramethyl-N-(2-(2-oxo-2-(1-(thiophen-2-yl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide,-   (89)    4-methoxy-N-(2-(2-(1-(3-methoxyphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-N,2,3,6-tetramethylbenzenesulfonamide,-   (90)    N-(2-(2-(1-(4-tert-butylphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,3,6-tetramethylbenzenesulfonamide,-   (91)    N-(2-(2-(6-((dimethylamino)methyl)-1-phenyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-N-isobutyl-4-methoxy-2,3,6-trimethylbenzene-sulfonamide,-   (92)    N-isobutyl-4-methoxy-2,3,6-trimethyl-N-(2-(2-oxo-2-(1-phenyl-6-(pyrrolidin-1-ylmethyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzene-sulfonamide,-   (93)    N-isobutyl-4-methoxy-2,3,6-trimethyl-N-(2-(2-oxo-2-(1-phenyl-6-(piperidin-1-ylmethyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzene-sulfonamide,-   (94)    N-isobutyl-4-methoxy-2,3,6-trimethyl-N-(2-(2-(6-(morpholinomethyl)-1-phenyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)benzene-sulfonamide,-   (95)    N-(2-(2-(1-benzyl-6-((dimethylamino)methyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-N-isobutyl-4-methoxy-2,3,6-trimethylbenzene-sulfonamide,-   (96)    N-(2-(2-(6-((dimethylamino)methyl)-1-phenethyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-N-isobutyl-4-methoxy-2,3,6-trimethyl-benzenesulfonamide,-   (97)    N-(2-(2-(1-butyl-6-((dimethylamino)methyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-N-isobutyl-4-methoxy-2,3,6-trimethylbenzene-sulfonamide,-   (98)    N-(2-(2-(6-((dimethylamino)methyl)-1-(thiophen-2-yl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-N-isobutyl-4-methoxy-2,3,6-trimethyl-benzenesulfonamide,-   (99)    N-(2-(2-(6-((dimethylamino)methyl)-1-ethyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-N-isobutyl-4-methoxy-2,3,6-trimethylbenzene-sulfonamide,-   (100)    N-(2-(2-(1-ethyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-N-isobutyl-4-methoxy-2,3,6-trimethylbenzenesulfonamide,-   (101)    N-isobutyl-4-methoxy-2,3,6-trimethyl-N-(2-(2-oxo-2-(1-propyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide,-   (102)    N-isobutyl-N-(2-(2-(1-isopropyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-2,3,6-trimethylbenzenesulfonamide,-   (103)    N-(2-(2-(1-ethyl-6-methyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-N-isobutyl-4-methoxy-2,3,6-trimethylbenzenesulfonamide,-   (104)    N-isobutyl-N-(2-(2-(1-isopropyl-6-methyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-2,3,6-trimethylbenzenesulfonamide,-   (105)    N-(2-(2-(6-((dimethylamino)methyl)-1-phenyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,3,5-tetramethylbenzene-sulfonamide,-   (106)    4-methoxy-N,2,3,5-tetramethyl-N-(2-(2-oxo-2-(1-phenyl-6-(pyrrolidin-1-ylmethyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzene-sulfonamide,-   (107)    4-methoxy-N,2,3,5-tetramethyl-N-(2-(2-oxo-2-(1-phenyl-6-(piperidin-1-ylmethyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzene-sulfonamide,-   (108)    4-methoxy-N,2,3,5-tetramethyl-N-(2-(2-(6-(morpholinomethyl)-1-phenyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)benzenesulfonamide,-   (109)    N-(2-(2-(1-benzyl-6-((dimethylamino)methyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,3,5-tetramethylbenzene-sulfonamide,-   (110)    N-(2-(2-(6-((dimethylamino)methyl)-1-phenethyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,3,5-tetramethylbenzene-sulfonamide,-   (111)    N-(2-(2-(1-butyl-6-((dimethylamino)methyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,3,5-tetramethylbenzene-sulfonamide,-   (112)    N-(2-(2-(6-((dimethylamino)methyl)-1-(thiophen-2-yl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,3,5-tetramethylbenzene-sulfonamide,-   (113)    N-(2-(2-(6-((dimethylamino)methyl)-1-ethyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,3,5-tetramethylbenzenesulfonamide,-   (114)    N-(2-(2-(1-ethyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,3,5-tetramethylbenzenesulfonamide,-   (115)    4-methoxy-N,2,3,5-tetramethyl-N-(2-(2-oxo-2-(1-propyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide,-   (116)    N-benzyl-4-methoxy-2,3,6-trimethyl-N-(2-(2-oxo-2-(1-phenyl-6-(pyrrolidin-1-ylmethyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzene-sulfonamide,-   (117)    N-benzyl-4-methoxy-2,3,6-trimethyl-N-(2-(2-(6-(morpholinomethyl)-1-phenyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)benzene-sulfonamide,-   (118)    N-benzyl-N-(2-(2-(1-benzyl-6-((dimethylamino)methyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-2,3,6-trimethylbenzene-sulfonamide,-   (119)    N-benzyl-N-(2-(2-(6-((dimethylamino)methyl)-1-phenethyl-3,4-dihydropyrrolo-[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-2,3,6-trimethylbenzene-sulfonamide,-   (120)    N-benzyl-N-(2-(2-(1-butyl-6-((dimethylamino)methyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)-ethyl)-4-methoxy-2,3,6-trimethylbenzene-sulfonamide,-   (121)    N-benzyl-N-(2-(2-(6-((dimethylamino)methyl)-1-(thiophen-2-yl)-3,4-dihydro-pyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-2,3,6-trimethyl-benzenesulfonamide,-   (122)    N-benzyl-N-(2-(2-(6-((dimethylamino)methyl)-1-ethyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethyl)ethyl)-4-methoxy-2,3,6-trimethylbenzene-sulfonamide,-   (123)    N-benzyl-4-methoxy-2,3,6-trimethyl-N-(2-(2-oxo-2-(1-propyl-3,4-dihydro-pyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide,-   (124)    N-benzyl-N-(2-(2-(1-isopropyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-2,3,6-trimethylbenzenesulfonamide,-   (125)    N-benzyl-4-methoxy-2,6-dimethyl-N-(2-(2-oxo-2-(1-phenethyl-3,4-dihydro-pyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide,-   (126)    N-benzyl-N-(2-(2-(6-((dimethylamino)methyl)-1-phenyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-2,6-dimethylbenzenesulfonamide,-   (127)    N-benzyl-4-methoxy-2,6-dimethyl-N-(2-(2-oxo-2-(1-phenyl-6-(pyrrolidin-1-ylmethyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzene-sulfonamide,-   (128)    N-benzyl-4-methoxy-2,6-dimethyl-N-(2-(2-oxo-2-(1-phenyl-6-(piperidin-1-ylmethyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzene-sulfonamide,-   (129)    N-benzyl-N-(2-(2-(1-benzyl-6-((dimethylamino)methyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2-(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-2,6-dimethylbenzene-sulfonamide,-   (130)    N-benzyl-N-(2-(2-(6-((dimethylamino)methyl)-1-(thiophen-2-yl)-3,4-dihydro-pyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-2,6-dimethyl-benzenesulfonamide,-   (131)    N-benzyl-N-(2-(2-(6-((dimethylamino)methyl)-1-ethyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-2,6-dimethylbenzene-sulfonamide,-   (132)    N-benzyl-N-(2-(2-(1-ethyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-2,6-dimethylbenzenesulfonamide,-   (133)    4-methoxy-N,2,6-trimethyl-N-(2-(2-oxo-2-(1-phenethyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide,-   (134)    N-(2-(2-(1-butyl-6-((dimethylamino)methyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,6-trimethylbenzenesulfonamide,-   (135)    N-(2-(2-(1-ethyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,6-trimethylbenzenesulfonamide,-   (136)    4-methoxy-N,2,6-trimethyl-N-(2-(2-oxo-2-(1-propyl-3,4-dihydropyrrolo[1,2-a]-pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide,-   (137)    N-(2-(2-(1-isopropyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,6-trimethylbenzenesulfonamide,-   (138)    N-(2-(2-(1-ethyl-6-methyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,6-trimethylbenzenesulfonamide,-   (139)    N-(2-(2-(6-((dimethylamino)methyl)-1-phenyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-N,2,4,6-tetramethylbenzenesulfonamide,-   (140)    N,2,4,6-tetramethyl-N-(2-(2-oxo-2-(1-phenyl-6-(pyrrolidin-1-ylmethyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide,-   (141)    N,2,4,6-tetramethyl-N-(2-(2-oxo-2-(1-phenyl-6-(piperidin-1-ylmethyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide,-   (142)    N,2,4,6-tetramethyl-N-(2-(2-(6-(morpholinomethyl)-1-phenyl-3,4-dihydro-pyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)benzenesulfonamide,-   (143)    N-(2-(2-(1-benzyl-6-((dimethylamino)methyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-N,2,4,6-tetramethylbenzenesulfonamide,-   (144)    N-(2-(2-(6-((dimethylamino)methyl)-1-(thiophen-2-yl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-N,2,4,6-tetramethylbenzene-sulfonamide,-   (145)    N-(2-(2-(6-((dimethylamino)methyl)-1-ethyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-N,2,4,6-tetramethylbenzenesulfonamide,-   (146)    N,2,4,6-tetramethyl-N-(2-(2-oxo-2-(1-propyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide,-   (147)    N-(2-(2-(1-isopropyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-N,2,4,6-tetramethylbenzenesulfonamide,-   (148)    4-methoxy-N,2,3,6-tetramethyl-N-(2-(2-oxo-2-(1-phenethyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide,-   (149)    4-methoxy-N,2,3,6-tetramethyl-N-(2-(2-oxo-2-(1-phenyl-6-(piperidin-1-ylmethyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzene-sulfonamide,-   (150)    4-methoxy-N,2,3,6-tetramethyl-N-(2-(2-(6-(morpholinomethyl)-1-phenyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)benzenesulfonamide,-   (151)    N-(2-(2-(1-benzyl-6-((dimethylamino)methyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,3,6-tetramethylbenzene-sulfonamide,-   (152)    N-(2-(2-(1-ethyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,3,6-tetramethylbenzenesulfonamide,-   (153)    N-(2-(2-(1-isopropyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,3,6-tetramethylbenzenesulfonamide,-   (154)    N-benzyl-4-methoxy-2,6-dimethyl-N-(2-(2-oxo-2-(1-propyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide,-   (155)    N-benzyl-N-(2-(2-(1-isopropyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-2,6-dimethylbenzenesulfonamide,-   (156)    N-(3-(6-(2-(4-methylpiperazin-1-yl)ethyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-3-oxo-1-phenylpropyl)naphthalin-2-sulfonamide,-   (157)    N-(3-(6-(2-morpholinoethyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-3-oxo-1-phenylpropyl)naphthalin-2-sulfonamide,-   (158)    4-methoxy-N,2,6-trimethyl-N-(2-(2-oxo-2-(6-(2-(pyrrolidin-1-yl)ethyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide,-   (159)    N-(3-oxo-1-phenyl-3-(6-(2-(pyrrolidin-1-yl)ethyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)propyl)naphthalene-2-sulfonamide,-   (160)    4-methoxy-N,2,6-trimethyl-N-(2-(2-(6-(2-(4-methylpiperazin-1-yl)ethyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)benzenesulfonamide,-   (161)    4-methoxy-N,2,6-trimethyl-N-(2-(2-(6-(2-morpholinoethyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)benzenesulfonamide,-   (162)    N-((1R)-3-(1-Ethyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-3-oxo-1-phenylpropyl)naphthalene-2-sulfonamide,-   (163)    4-Methoxy-N,2,6-trimethyl-N-(2-(2-oxo-2-(3-(piperidin-1-ylmethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)ethoxy)ethyl)benzene-sulfonamide,-   (164)    (R)—N-(3-oxo-1-phenyl-3-(3-(piperidin-1-ylmethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)propyl)naphthalene-2-sulfonamide,-   (165)    4-Methoxy-N,2,6-trimethyl-N-(2-(2-oxo-2-(6-(pyridin-4-ylmethyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide,-   (166)    4-Methoxy-N,2,6-trimethyl-N-(2-(2-oxo-2-(6-(pyridin-3-yl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide,-   (167)    N-(3-Oxo-1-phenyl-3-(6-(pyridin-3-yl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)propyl)naphthalene-2-sulfonamide,-   (168)    N-(3-Oxo-1-phenyl-3-(6-(pyridin-4-yl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)propyl)naphthalene-2-sulfonamide,-   (169)    N-(3-Oxo-1-phenyl-3-(6-(pyridin-4-ylmethyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)propyl)naphthalene-2-sulfonamide,-   (170)    4-Methoxy-N,2,6-trimethyl-N-(2-(2-oxo-2-(6-(2-(pyridin-3-yl)ethyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide,-   (171)    N-(3-Oxo-1-phenyl-3-(6-(2-(pyridin-3-yl)ethyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)propyl)naphthalene-2-sulfonamide,-   (172)    4-Methoxy-N,2,6-trimethyl-N-(2-(2-oxo-2-(6-(2-(pyridin-4-yl)ethyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide,-   (173)    N-(3-Oxo-1-phenyl-3-(6-(2-(pyridin-4-yl)ethyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)propyl)naphthalene-2-sulfonamide,-   (174)    4-Methoxy-N,2,6-trimethyl-N-(2-(2-oxo-2-(6-(pyridin-3-ylmethyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide,-   (175)    4-Methoxy-N,2,6-trimethyl-N-(2-(2-oxo-2-(2-(pyridin-4-yl)-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)ethoxy)ethyl)benzenesulfonamide,-   (176)    N-(3-Oxo-1-phenyl-3-(6-(pyridin-3-ylmethyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)propyl)naphthalene-2-sulfonamide,-   (177)    4-Methoxy-N,2,6-trimethyl-N-(2-(2-oxo-2-(6-(pyridin-4-yl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide,-   (178)    4-Methoxy-N,2,6-trimethyl-N-(2-(2-oxo-2-(2-(2-(pyridin-4-yl)ethyl)-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)ethoxy)ethyl)benzenesulfonamide    and-   (179)    4-Methoxy-N,2,6-trimethyl-N-(2-(2-oxo-2-(2-(pyridin-4-ylmethyl)-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)ethoxy)ethyl)benzenesulfonamide    in the form of an individual enantiomer or an individual    diastereomer, in the form of the racemate, enantiomers,    diastereomers, mixtures of the enantiomers or diastereomers, in each    case in the form of their bases and/or physiologically compatible    salts.

The numbering adopted above of the individual embodiments of thecompounds according to the invention is retained in the followingdiscussions of the present invention, in particular in the descriptionof the examples.

The compounds according to the invention exhibit an antagonistic actionon the human B1R receptor or on the B1R receptor of rats. In a preferredembodiment of the invention the compounds according to the inventionexhibit an antagonistic action on both the human B1R receptor (hB1R) andthe B1R receptor of rats (rB1R).

Particularly preferred are compounds which at a concentration of 10 μMin the FLIPR assay exhibit an inhibition on the human B1R receptorand/or on the B1R receptor of rats of at least 15%, preferably at least25%, more preferably at least 50%, still more preferably at least 70%,most preferably at least 80% and especially preferably at least 90%.

Particularly preferred are compounds that in a concentration of 10 μMexhibit an inhibition on the human B1R receptor and on the B1R receptorof rats of at least 70%, especially at least 80% and particularlypreferably at least 90%.

The agonistic or antagonistic action of compounds can be quantified onthe bradykinin 1 receptor (B1R) of humans and rats with ectopicallyexpressing cell lines (CHO K1 cells) and with the aid of aCa²⁺-sensitive dye (Fluo-4) in the fluorescent imaging plate reader(FLIPR). The figure in percent activation refers to the Ca²⁺ signalafter addition of Lys-Des-Arg⁹-bradykinin (0.5 nM) andDes-Arg⁹-bradykinin (100 nM). Antagonists result in a suppression of theCa²⁺ inflow after the addition of the agonist. Percent inhibition valuesare given in comparison to the maximum achievable inhibition.

The compounds according to the invention act, for example, on theBradykinin 1 receptor (B1R), which is implicated in connection withvarious disorders or disease states, which means that they are useful aspharmaceutically active ingredients in pharmaceutical compositions(i.e., medicaments). The present invention therefore also providesmedicaments containing at least one substituted sulfonamide compoundaccording to the invention as well as optionally suitable additivesand/or auxiliary substances and/or optionally further active substances.These medicaments are particularly suitable for treating pain, inparticular acute, visceral, neuropathic, chronic pain and/orinflammatory pain. Moreover, these medicaments are also suitable fortreating diabetes, diseases of the respiratory tract, inflammatoryintestinal diseases, neurological diseases, inflammation of the skin,rheumatic diseases, septic shock, reperfusion syndrome, obesity, and asan angiogenesis inhibitor.

In addition to at least one substituted sulfonamide compound accordingto the invention, the medicaments according to the invention optionallyalso contain suitable additives and/or auxiliary substances, thus alsocarrier materials, fillers, solvents, diluents, colourants and/orbinders, and can be administered as liquid medicament forms in the formof injections for solution, drops or juices, as semi-solid medicamentforms in the form of granules, tablets, pellets, patches, capsules,plasters/spray plasters or aerosols. The choice of the auxiliarysubstances, etc. as well as the amounts thereof to be used depend onwhether the medicament is to be administered orally, parenterally,intravenously, intraperitoneally, intradermally, intramuscularly,nasally, buccally, rectally or topically, for example to the skin,mucous membranes or to the eyes. For oral application suitable arepreparations in the form of tablets, pills, capsules, granules, drops,juices and syrups, while for parenteral, topical and inhalativeapplication suitable preparations are in the form of solutions,suspensions, easily reconstitutable dry preparations as well as sprays.Sulfonamide compounds according to the invention in depot form, indissolved form or in a plaster, optionally with the addition of agentspromoting penetration of the skin, are suitable percutaneous applicationpreparations. Orally or percutaneously usable preparation forms canprovide for the delayed release of the substituted sulfonamide compoundsaccording to the invention. The substituted sulfonamide compoundsaccording to the invention can also be used in parenteral long-termdepot forms, such as for example implants or implanted pumps. Inprinciple other active constituents known to the person skilled in theart can be added to the medicaments according to the invention.

The amount of active constituent to be administered to the patientvaries depending on the patient's weight, type of application, medicalindications and the severity of the illness. Normally 0.00005 to 50mg/kg, in particular 0.01 to 5 mg/kg of at least one substitutedsulfonamide compound according to the invention are administered.

In a preferred form of the medicament a contained substitutedsulfonamide compound according to the invention may be present as a pure(isolated) diastereomer and/or enantiomer, as a racemate, or as anon-equimolar or equimolar mixture of the diastereomers and/orenantiomers.

B1R is involved in particular in the phenomenon of pain. Accordingly,the substituted sulfonamide compounds according to the invention can beused for the preparation of a medicament for treating pain, inparticular acute, visceral, neuropathic or chronic pain. The inventionaccordingly also provides the use of a substituted sulfonamide compoundaccording to the invention for the preparation of a medicament fortreating pain, in particular acute, visceral, neuropathic or chronicpain. Moreover, the present invention also provides the use of asubstituted sulfonamide compound according to the invention for thepreparation of a medicament for the treatment of inflammatory pain.

The present invention also provides the use of a substituted sulfonamidecompound according to the invention for the preparation of a medicamentfor treating diabetes, diseases of the respiratory tract, inflammatoryintestinal diseases, neurological diseases, inflammation of the skin,rheumatic diseases, septic shock, reperfusion syndrome, obesity, and asan angiogenesis inhibitor.

In this connection it may be preferred in one of the above uses if anemployed substituted sulfonamide compound is present as a purediastereomer and/or enantiomer, as a racemate, or as a non-equimolar orequimolar mixture of the diastereomers and/or enantiomers.

The invention also provides a method for treating, in particular in oneof the aforementioned medical indications, a non-human mammal or aperson that requires treatment for pain, in particular chronic pain, byadministration of a therapeutically active dose of a substitutedsulfonamide compound according to the invention or a medicamentaccording to the invention.

The invention also provides a method for treating, in particular in oneof the aforementioned medical indications, a non-human mammal or aperson that requires treatment thereof, by administration of atherapeutically active dose of a substituted sulfonamide compoundaccording to the invention or a medicament according to the invention.

The invention also provides a method for the preparation of thesubstituted sulfonamide compounds according to the invention asexplained and illustrated in the following description, examples as wellas the claims.

General Process for Preparing Substituted Sulfonamide Compounds of theInvention:

The carboxylic acids N are converted in an amide formation using primaryor secondary amines O in the presence of water-removing agents such assodium or magnesium sulfate, phosphorus oxide or reagents such as forexample CDI, DCC (optionally polymer-bound), TBTU, EDCI, PyBOP orPFPTFA, also in the presence of HOAt or HOBt and an organic base, forexample DIPEA or pyridine, in an organic solvent such as THF,dichloromethane, diethyl ether, dioxane, DMF or acetonitrile, attemperatures from 0° C. to the reflux temperature, to form the finalproducts corresponding to formula P.

General Process for the Preparation of the Acids N

In Method I the racemic (R and S configuration) or enantiomer-pure (R orS configuration) aminoalcohols A are reacted in a sulfonylation withsulfonyl chlorides, bromides or pentafluorophenylate R¹SO₂X (X═Cl, Br,OPFP), optionally in the presence of an organic or inorganic base, forexample potassium carbonate, sodium carbonate, sodium hydrogencarbonate, diisopropylethylamine, triethylamine, pyridine,dimethylaminopyridine, diethylamine or DBU, preferably in an organicsolvent, for example acetone, acetonitrile, dichloromethane ortetrahydrofuran and at a temperature from 0° to the reflux temperature,to form the sulfonylated aminoalcohols B.

The sulfonylated aminoalcohols B are reacted in an alkylation reactionwith halogenated ester compounds using tetrabutylammonium chloride orbromide or tetrabutylammonium hydrogen sulfate in a phase transferreaction using an organic solvent such as THF, toluene, benzene orxylene and inorganic bases such as potassium hydroxide, sodiumhydroxide, sodium carbonate, sodium hydrogen carbonate, potassiumcarbonate or in the presence of an organic or inorganic base,conventional inorganic bases being metal alcoholates such as sodiummethanolate, sodium ethanolate, potassium tert-butylate, lithium orsodium bases such as lithium diisopropylamide, butyllithium,tert-butyllithium, sodium methylate or metal hydrides such as potassiumhydride, lithium hydride, sodium hydride, conventional organic basesbeing diisopropylethylamine, triethylamine, in an organic solvent suchas dichloromethane, THF or diethyl ether, at 0° C. to the refluxtemperature, to form the products of the general structure C.

In Method II the racemic (R and S configuration) or enantiomer-pure (Ror S configuration) aminoalcohols E are reacted in a sulfonylation withsulfonyl chlorides, bromides or pentafluorophenolate R¹SO₂X (X═Cl, Br,OPFP), optionally in the presence of an organic or inorganic base, forexample potassium carbonate, sodium hydrogen carbonate,diisopropylethylamine, triethylamine, pyridine, dimethylaminopyridine,diethylamine or DBU, preferably in an organic solvent, for exampleacetone, acetonitrile, dichloromethane or tetrahydrofuran and at atemperature from 0° to the reflux temperature, to form the sulfonylatedaminoalcohols F. The sulfonylated aminoalcohols F are then reacted in analkylysation reaction with alkyl halides (RX, X=1, Br, Cl), mesylates oralternative alkylation reagents, optionally in the presence of anorganic or inorganic base, for example sodium hydride, potassiumcarbonate, cesium carbonate, DBU or DIPEA, preferably in an organicsolvent, for example dimethylformamide, acetone, THF, acetonitrile,dioxane or mixtures of these solvents, at a temperature from 0° C. tothe reflux temperature, to form the sulfonylated aminoalcohols B.

In Method III the racemic (R and S configuration) or enantiomer-pure (Ror S configuration) acids G are esterified using water-extractingreagents, for example inorganic acids such as H₂SO₄ or phosphorus oxidesor organic reagents such as thionyl chloride, in organic solvents suchas THF, diethyl ether, methanol, ethanol or dichloromethane, to thestage H, at temperatures from room temperature to reflux temperatures.The amino acid esters H are reacted in a sulfonylation with sulfonylchlorides, bromides or pentafluorophenolate R¹SO₂X (X═Cl, Br, OPFP),optionally in the presence of an organic or inorganic base, for examplepotassium carbonate, sodium carbonate, sodium hydrogen carbonate,diisopropylethylamine, triethylamine, pyridine, dimethylaminopyridine,diethylamine or DBU, preferably in an organic solvent, for exampleacetone, acetonitrile, dichloromethane or tetrahydrofuran and at atemperature from 0° C. to the reflux temperature, to form thesulfonylated aminoesters I.

In the Methods I-III the ester compounds C and I are reacted in an estercleavage using organic acids such as trifluoroacetic acid or aqueousinorganic acids such as hydrochloric acid, or using aqueous inorganicbases such as lithium hydroxide, potassium hydroxide, potassiumhydroxide, sodium hydroxide, sodium carbonate, sodium hydrogencarbonate, potassium carbonate in organic solvents such as methanol,dioxane, dichloromethane, THF, diethyl ether or mixtures of thesesolvents, at 0° C. to room temperature, to form the acid stagescorresponding to formula D (acid building blocks S1-S8).

General Processes for Preparing the Amines O

Pyrrole A is dissolved in a suitable solvent, such as for exampleethanol, methanol, 2-butanone, DMSO, diethyl ether, water, benzene,toluene, THF, DCM, acetonitrile, acetone, DMF or pentane or a mixture ofthese solvents, and a suitable base is added, such as for examplepotassium hydroxide, sodium hydroxide, optionally in aqueous oralcoholic solution, potassium carbonate, potassium hexamethyldisilazane,sodium hydride, potassium hydride, sodium methanolate, sodiumethanolate, sodium tert. butylate or diisopropylethylamine, optionallywith the addition of an auxiliary substance such as for example18-crown-6,15-crown-5, tetrabutylammonium bromide or sulfate,benzyltriethylammonium chloride, 1-n-butyl-3-methylimidazoliumtetrafluoroborate or DMAP, followed by reaction with the correspondingiodide, bromide or chloride compound to form the stage B.

The ring closure to form the 1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine Cis carried out by reacting the 2-(1H-pyrrol-1-yl)ethanamine with thecorresponding aldehyde in solvents such as acetic acid, ethanol,methanol, pyridine, benzene, toluene, DCM or a mixture of thesesolvents, optionally with the addition of benzotriazole, aluminiumtrichloride or p-toluenesulfonic acid and optionally with removal byazeotropic distillation of the water formed in the reaction. Thereaction times can be between 1 and 48 hours and the reactiontemperature can vary between 20° C. and 110° C.

The ring closure to form the 1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazinestage C can however also be achieved by reacting the2-(1H-pyrrol-1-yl)ethanamine with the corresponding carboxylic acidfollowed by reduction of the initially formed cyclic imine D withreducing agents, such as for example sodium boron hydride.

Starting from 1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazines, for furtherderivatisations on the pyrrole part the nitrogen in the piperidine partmust if necessary be protected. Various protective groups are suitablefor this purpose, such as for example BOC, Cbz or Fmoc protectivegroups.

The introduction of the BOC protective group by means of di-tert.-butyldicarbonate can be carried out in solvents such as for example dioxane,DCM, THF, DMF, water, benzene, toluene, methanol, acetonitrile ormixtures of these solvents, optionally with the addition of sodiumhydroxide, triethylamine, diisopropylethylamine, sodium hydrogencarbonate, sodium carbonate or DMAP at temperatures between 0° C. and100° C. The Cbz protective group can be introduced by reacting benzylchloroformate in solvents such as for example diethyl ether, THF, DMF,benzene, toluene, dioxane, water, acetone, ethyl acetate, DCM orchloroform, optionally with the addition of a base such as for examplesodium carbonate, sodium hydrogen carbonate, potassium carbonate, sodiumhydroxide or triethylamine, optionally with the addition of a couplingreagent, such as for example HOBt. The Fmoc protective group isintroduced by reacting 9H-fluoren-9-yl methylchloroformate in solventssuch as for example DCM, DCE, diethyl ether, THF, dioxane, acetone,acetonitrile, DMF or water, optionally with the addition of a base, suchas for example diisopropylethylamine, triethylamine, pyridine,N-methylmorpholine, sodium carbonate or sodium hydrogen carbonate andoptionally under microwave irradiation.

The introduction of the amino methyl substituent on the pyrrole ring iscarried out via an aminoalkylation to form the stages F. For theaminoalkylation the corresponding aromatic compound can be reacted withformaldehyde and the corresponding amine in ethanol or methanol. Avariant of this process uses the reaction of an iminium salt with thecorresponding aromatic system to form the stage E. The iminium salt isobtained for example by cleavage of the corresponding aminal.

The aminal is formed by reacting the corresponding amine withformaldehyde. The reaction can be carried out in solvents such as forexample water, methanol, ethanol, tert.-butanol, benzene, toluene,diethyl ether, dioxane, THF, chloroform, DCM, DMF, acetonitrile, diluteaqueous HCl solution or mixtures of these solvents, optionally with theaddition of a base, such as for example potassium carbonate or sodiumhydroxide.

The iminium salt is obtained by reacting the aminal with for exampleacetyl or benzoyl chloride, mesyl chloride, trimethylsilyl chloride oriodide, tetrachlorosilane or borone trifluoride etherate, in solventssuch as for example carbon tetrachloride, chloroform, DCM, diethylether, DMF, acetonitrile, hexane or DME at a temperature between −80° C.and +25° C.

The subsequent aminoalkylation to the stages F can be carried out insolvents such as for example acetonitrile, THF, DCM, diethyl ether,toluene or benzene at temperatures between −78° C. and room temperature.

The aminoalkylated 5,6,7,8-tetrahydropyrrolo[1,2-a]pyrazine compound Gused as building block is obtained by cleavage of the correspondingprotective group.

BOC protective groups can be removed, for example, by reaction with HClin organic solvents such as dioxane, methanol, ethanol, acetonitrile orethyl acetate, or by reaction with TFA or methanesulfonic acid indichloromethane or THF, at a temperature from 0° C. to 110° C. and areaction time of 0.5 to 20 hours.

The Cbz protective group can be removed, for example, under acidicconditions. This acidic cleavage can be carried out for example byreaction with an HBr/glacial acetic acid mixture, a mixture of TFA indioxane/water or HCl in methanol or ethanol. Also suitable however arereagents such as for example Me₃Sil in solvents such as for example DCM,chloroform or acetonitrile, BF₃ etherate with the addition ofethanethiol or Me₂S in solvents such as for example DCM, a mixture ofaluminium chloride/anisole in a mixture of DCM and nitromethane, ortriethylsilane/PdCl₂ in methanol with the addition of triethylamine. Afurther method is the hydrogenolytic cleavage of the protective group atelevated pressure or without the use of pressure, by means of catalystssuch as for example Pd on charcoal, Pd(OH)₂, PdCl₂, Raney nickel or PtO₂in solvents such as for example methanol, ethanol, 2-propanol, THF,acetic acid, ethyl acetate, chloroform, optionally with the addition ofHCl, formic acid or TFA.

The Fmoc protective group is as a rule removed under basic conditions insolvents such as for example acetonitrile, DMF, THF, diethyl ether,methanol, ethanol, 1-octanethiol, DMC or chloroform. Suitable bases arefor example diethylamine, piperidine, 4-aminomethylpiperidine,pyrrolidine, DBU, NaOH or LiOH. Reagents such as for example Ag₂O/Melcan however also be used.

Starting from the protected 1,2,3,4-tetrahydropyrrolo[1,2]a]pyrazine Ean aldehyde function is first of all introduced in the pyrrole ring in aVilsmeier reaction. The Vilsmeier reaction is carried out by reactingHCN and HCl in CHCl₃ or diethyl ether or a mixture of these solvents.Further suitable reagents for the Vilsmeier reaction are DMF and oxalylchloride or POCl₃ in solvents such as for example DCM or DCE, but alsofor example trimethoxyethane and TiCl₄ in DCM.N-(chloromethylene)-N-methylmethane aminium chloride with the additionof NaOH can also be used.

The subsequent Wittig reaction to the stages I, using phosphorylideneand a strong base, for example potassium tert.-butylate, n-butyllithium,s-butyllithium, phenyllithium, lithium diisopropylamide or lithiumhexamethyldisilazide in organic solvents such as THF, diethyl ether,cyclohexane, toluene or a mixture of these solvents at a temperaturefrom −78° C. to +30° C. yields the corresponding unsaturated esters.

The reduction of the double bond can be carried out hydrogenolyticallyor by adding suitable reducing agents. Heterogeneous catalysts as wellas homogeneous catalysts can be used in the hydrogenolysis. Suitableheterogeneous catalysts are for example Pd on charcoal or Raney nickelin solvents such as for example methanol, ethanol, toluene, THF, ethylacetate, acetic acid or in mixtures of these solvents, optionally withthe addition of bases such as for example triethylamine. The reactioncan be carried out at atmospheric pressure or at elevated pressure. Asuitable homogeneous catalyst is for example (PPh₃)₃RhCl in benzene ortoluene. A suitable reducing agent is for example NaBH₄ with theaddition of NiCl₂ in the solvents such as for example methanol, ethanol,THF or mixtures of these solvents.

The reduction of the ester group for the preparation of the stages K canbe carried out by reduction with reducing agents such as for exampleDIBAHL-H in solvents such as for example THF, DCM, toluene or hexane attemperatures between −78° C. and room temperature.

In the subsequent reductive amination to the stages L the aldehyde isreacted with an amine and the imine thereby formed is then reduced tothe amine. Suitable reducing agents are for example NaBH₄, NaBH(OAc)₃,NaCNBH₃, NH₄CNBH₃, polymer-bound cyanoboron hydride, borane-pyridinecomplex or triethylsilane. The reaction can be carried out in solventssuch as for example methanol, ethanol, DCM, DCE, acetonitrile, THF,toluene, water, DMSO, DMF, 1-methyl-2-pyrrolidin-2-one or mixtures ofthese solvents. Auxiliary reagents such as for example HCl (gaseous oras an aqueous solution), acetic acid, TFA, ZnCl₂,1,3-dimethyl-2-imidazolidine, MgSO₄, Na₂SO₄ or molecular sieves are alsoused. The imine that is formed can however also be converted to theamine by catalytic hydrogenation on catalysts such as for example PtO₂or Pd/C in solvents such as for example methanol or ethanol.

The compound M used as building block is obtained by cleavage of thecorresponding protective group. BOC protective groups can be eliminated,for example, by reaction with HCl in organic solvents such as dioxane,methanol, ethanol, acetonitrile or ethyl acetate, or by reaction withTFA or methanesulfonic acid in dichloromethane or THF at a temperaturefrom 0° C. to 110° C. and a reaction time of 0.5 to 20 hours. The Cbzprotective group can be removed, for example, under acidic conditions.This acidic cleavage can be carried out for example by reaction with anHBr/glacial acetic acid mixture, a mixture of TFA in dioxane/water orHCl in methanol or ethanol. Also suitable however are reagents such asfor example Me₃Sil in solvents such as for example DCM, chloroform oracetonitrile, BF₃ etherate with the addition of ethanethiol or Me₂S insolvents such as for example DCM, a mixture of aluminiumchloride/anisole in a mixture of DCM and nitromethane ortriethylsilane/PdCl₂ in methanol with the addition of triethylamine. Afurther method is the hydrogenolytic cleavage of the protective group atelevated pressure or without the use of pressure with the aid ofcatalysts such as for example Pd on charcoal, Pd(OH)₂ PdCl₂, Raneynickel or PtO₂ in solvents such as for example methanol, ethanol,2-propanol, THF, acetic acid, ethyl acetate, chloroform, optionally withthe addition of HCl, formic acid or TFA. The Fmoc protective group is asa rule removed under basic conditions in solvents such as for exampleacetonitrile, DMF, THF, diethyl ether, methanol, ethanol, 1-octanethiol,DCM or chloroform. Suitable bases are for example diethylamine,piperidine, 4-aminomethylpiperidine, pyrrolidine, DBU, NaOH or LiOH.Reagents such as for example Ag₂O/Mel can however also be used.

The nitrogen on the piperidine part of the alkyl5,6,7,8-tetrahydroimidazo[1,2]a]-pyrazin-2-carboxylate of stage A firstof all has to be protected for further reactions. Various protectivegroups, such as for example the BOC, Cbz or Fmoc protective group, aresuitable for this purpose. The introduction of the BOC protective groupby means of di-tert.-butyl dicarbonate can be carried out in solventssuch as for example dioxane, DCM, THF, DMF, water, benzene, toluene,methanol, acetonitrile or mixtures of these solvents, optionally withthe addition of sodium hydroxide, triethylamine, diisopropyl-ethylamine,sodium hydrogen carbonate, sodium carbonate or DMAP at temperaturesbetween 0° C. and 100° C. The Cbz protective group can be introduced bythe reaction of benzyl chloroformate in solvents such as for examplediethyl ether, THF, DMF, benzene, tolulene, dioxane, water, acetone,ethyl acetate, DCM or chloroform, optionally with the addition of abase, such as for example sodium carbonate, sodium hydrogen carbonate,potassium carbonate, sodium hydroxide or triethylamine, optionally withthe addition of a coupling reagent such as for example HOBt. The Fmocprotective group is introduced by reacting 9H-fluoren-9-ylmethylchloroformate in solvents such as for example DCM, DCE, diethylether, THF, dioxane, acetone, acetonitrile, DMF or water, optionallywith the addition of a base, such as for example diisopropylethylamine,triethylamine, pyridine, N-methylmorpholine, sodium carbonate or sodiumhydrogen carbonate and optionally under microwave irradiation.

The reduction of the ester group for the preparation of the stages C canbe carried out by reduction with reducing agents such as for exampleDIBAHL-H in solvents such as for example THF, DCM, toluene or hexane attemperatures between −78° C. and room temperature.

In the subsequent reductive amination for the preparation of the stagesD, the aldehyde is reacted with an amine and the formed imine is thenreduced to the amine.

Suitable reducing agents are for example NaBH₄, NaBH(OAc)₃, NaCNBH₃,NH₄CNBH₃, polymer-bound cyano boron hydride, borane-pyridine complex ortriethylsilane. The reaction can be carried out in solvents such as forexample methanol, ethanol, DCM, DCE, acetonitrile, THF, toluene, water,DMSO, DMF, 1-methyl-2-pyrrolidin-2-one or mixtures of these solvents.Often auxiliary reagents such as for example HCl (gaseous or as anaqueous solution), acetic acid, TFA, ZnCl₂,1,3-dimethyl-2-imidazolidine, MgSO₄, Na₂SO₄ or molecular sieves are alsoused. The formed imine can however also be converted to the amine bycatalytic hydrogenation on catalysts such as for example PtO₂ or Pd/C insolvents such as for example methanol or ethanol.

The aminoalkylated compound E used as building block is obtained bycleavage of the corresponding protective group. BOC protective groupscan be removed, for example, by reaction with HCl in organic solventssuch as dioxane, methanol, ethanol, acetonitrile or ethyl acetate, or byreaction with TFA or methanesulfonic acid in dichloromethane or THF at atemperature from 0° C. to 110° C. and a reaction time of 0.5 to 20hours. The Cbz protective group can be removed, for example, underacidic conditions. This acidic cleavage can be carried out for exampleby reaction with an HBr/glacial acetic acid mixture, a mixture of TFA indioxane/water or HCl in methanol or ethanol. Also suitable however arereagents such as for example Me₃Sil in solvents such as for example DCM,chloroform or acetonitrile, BF₃ etherate with addition of ethanethiol orMe₂S in solvents such as for example DCM, a mixture of aluminiumchloride/anisole in a mixture of DMC and nitromethane, ortriethylsilane/PdCl₂ in methanol with the addition of triethylamine. Afurther method is the hydrogenolytic cleavage of the protective group atelevated pressure or without pressure with the aid of catalysts such asfor example Pd on charcoal, Pd(OH)₂, PdCl₂, Raney nickel or PtO₂ insolvents such as for example methanol, ethanol, 2-propanol, THF, aceticacid, ethyl acetate, chloroform, optionally with the addition of HCl,formic acid or TFA. The Fmoc protective group is, as a rule, removedunder basic conditions in solvents such as for example acetonitrile,DMF, THF, diethyl ether, methanol, ethanol, 1-octanethiol, DCM orchloroform. Suitable bases are for example diethylamine, piperidine,4-aminomethylpiperidine, pyrrolidine, DBU, NaOH or LiOH. Reagents suchas for example Ag₂O/Mel can however also be used.

Pharmacological Investigations 1. Functional Investigation on theBradykinin 1 Receptor (B1R)

The agonistic or antagonistic action of substances can be determined onthe bradykinin 1 receptor (B1R) of humans and rats by means of thefollowing assay.

According to this assay the Ca²⁺ inflow through the channel isquantified by means of a Ca²⁺-sensitive dye (Fluo-4 type, MolecularProbes Europe BV, Leiden, Netherlands), in a Fluorescent Imaging PlateReader (FLIPR, Molecular Devices, Sunnyvale, USA). Method:

Chinese hamster ovary cells (CHO K1 cells) are used, which are stablytransfected with the human B1R gene (hB1R cells, Euroscreen s.a.,Gosselies, Belgium), or with the B1R gene of rats (rB1R cells, Axxam,Milan, Italy). For functional investigations these cells are plated outon black 96-well plates with a clear floor (BD Biosciences, Heidelberg,Germany) in a density of 20,000/25,000 cells/well. The cells areincubated overnight with 10 vol. % FBS (foetal bovine serum, GibcoInvitrogen GmbH, Karlsruhe, Germany) at 37° C. and 5% CO₂ in a culturemedium (hB1R cells: Nutrient Mixture Ham's F12, Gibco Invitrogen GmbH,Karlsruhe, Germany; rB1R cells: D-MEM/F12, Gibco Invitrogen GmbH,Karlsruhe, Germany). The following day the cells are charged for 60minutes at 37° C. with 2.13 μM Fluo-4 (Molecular Probes Europe BV,Leiden, Netherlands) in HBSS buffer (Hank's buffered saline solution,Gibco Invitrogen GmbH, Karlsruhe, Germany) together with 2.5 Mprobenecid (Sigma-Aldrich, Taufkirchen, Germany) and 10 mM HEPES(Sigma-Aldrich, Taufkirchen, Germany).

The plates are then washed twice with HBSS buffer and HBSS buffer isadded which additionally contains 0.1% BSA (bovine serum albumin;Sigma-Aldrich, Taufkirchen, Germany), 5.6 mM glucose and 0.05% gelatin(Merck KGaA, Darmstadt, Germany). After further incubation for 20minutes at room temperature the plates are used for the Ca²⁺ measurementin the FLIPR. The Ca²⁺-dependent fluorescence is measured both beforeand after the addition of substances (λ_(ex)=488 nm, λ_(em)=540 nm). Thequantification is carried out by measuring the highest fluorescenceintensity (FC, fluorescence counts) over time.

FLIPR Assay:

The FLIPR protocol consists of two substance additions. First of alltest substances (10 μM) are pipetted onto the cells and the Ca²⁺ inflowis compared with the control (hB1R: Lys-Des-Arg9-bradykinin 0.5 nM;rB1R: Des-Arg9-bradykinin 100 nM). This gives the result in percentactivation referred to the Ca²⁺ signal after addition ofLys-Des-Arg9-bradykinin (0.5 nM), bzw. Des-Arg9-bradykinin (100 nM).After 10 minutes' incubation 0.5 nM Lys-Des-Arg9-bradykinin (hB1R) and100 nM Des-Arg⁹-bradykinin (rB1R) are applied and the inflow of Ca²⁺ islikewise determined. Antagonists lead to a suppression of the Ca²⁺inflow. The percent inhibition compared to the maximum achievableinhibition is calculated. The compounds show a good activity on bothhuman and rat receptors.

The invention will be described in further detail hereinafter withreference to illustrative examples, which do not, however, restrict thescope of the invention.

EXAMPLES List of Abbreviations

Eq. Equivalent(s)Boc₂O Di-tert.-butyl dicarbonateCDI 1,1′-carbonyl diimidazole

d Day(s)

DCE 1,2-dichloroethane

DCM Dichloromethane

DIBAL-H Diisobutyl aluminium hydride

DIPEA Diisopropylethylamine DMF Dimethylformamide DMAP4-Dimethylaminopyridine

EDCI N-(3-Dimethylaminopropyl)-N′-ethyl-carbodiimidewt. % Weight percent

h Hour(s)

HATU O-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphateHOAt 1-hydroxy-7-azabenzotriazoleHOBt 1-hydroxy-1H-benzotriazolei.vac. In vacuo

M Molar

mbar Millibar

min Minute(s) N Normal

NaOH Sodium hydroxideRT Room temperatureB.p. Boiling point

THF Tetrahydrofuran

TFA Trifluoroacetic acid

Ms Methanesulfonyl

The following acid building blocks were used for the synthesis of thesulfonamide compounds according to the invention:

Acid building block Structure Name S1

{2-[(4-methoxy-2,6-dimethyl-benzenesulfonyl)-methyl-amino]-ethoxy}acetic acid S2

{2-[methyl-(2,4,6-trimethyl-benzenesulfonyl)-amino]- ethoxy}acetic acidS3

{2-[(4-methoxy-2,3,6-trimethyl-benzenesulfonyl)-methyl-amino]-ethoxy}acetic acid S4

{2-[benzyl-(4-methoxy-2,3,6-trimethyl-benzenesulfonyl)-amino]-ethoxy}acetic acid S5

2-[benzyl-(4-methoxy-2,6-dimethyl-benzenesulfonyl)- amino]-ethoxy}aceticacid S6

2-((4-methoxy-N,2,3,5- tetramethylphenylsulfonamido)methoxy)acetic acidS7

2-(2-(N-isobutyl-4-methoxy-2,3,6-trimethylphenylsulfonamido)ethoxy)acetic acid S8

3-(naphthalene-2-sulfonamido)-3-phenylpropionic acid S9

(R)-3-(Naphthalene-2-sulfonamido)-3- phenylpropanoic acid

Preparation of{2-[(4-methoxy-2,6-dimethyl-benzenesulfonyl)-methyl-amino]-ethoxy}aceticAcid S1

Stage 1. A solution of 3,5-dimethylanisole (102.5 g, 753 mmole) in DCM(1000 ml) was cooled to 0° C. A solution of chlorosulfonic acid (251 ml,3763 mmole) in DCM (250 ml) was added dropwise to this solution. After10 minutes' reaction time the reaction solution was poured into anicebath (1000 ml), and the phases were separated and extracted againwith DCM (250 ml). The combined organic phases were washed with water(1000 ml) and satd. NaCl solution (1000 ml), dried over Na₂SO₄ andconcentrated by evaporation. The product was purified by columnchromatography on silica gel (heptane/DCM 5:1). Yield: 63.5 g, 36%.Stage 2. 2-(methylamino)ethanol (3.8 ml), 46.9 mmole) was dissolved inDCM (200 ml) and triethylamine (15 ml, 107 mmole) was added. Thesolution was cooled to 0° C., a solution of4-methoxy-2,6-dimethylbenzene-1-sulfonyl chloride (10 g, 42.6 mmole)dissolved in DCM (100 ml) was added, and the whole was stirred for 1.5hours at RT. After completion of the reaction HCl (0.5 M, 100 ml) wasadded, the phases were separated, washed with water, dried over Na₂SO₄and concentrated by evaporation. The crude product was used withoutfurther purification in the next stage. Yield 12.2 g, >100%.Stage 3. n-Bu₄NCl (3.95 g, 14.2 mmole) was added to a solution ofN-2-(hydroxyethyl)-4-methoxy-N,2,6-trimethylbenzenesulfonamide (12.2max. 42.6 mmole) in toluene (250 ml). The reaction solution was cooledto 0° C. and NaOH solution (35%, 250 ml) was added. Tert.-butylbromoacetate (9.3 ml, 63.9 mmole) was added dropwise to this solutionand then stirred for 3 hours at RT. The organic phase was separated andwashed three times with water (300 ml), dried over Na₂SO₄ andconcentrated by evaporation. The crude product was used without furtherpurification in the next stage. Yield 17.95 g, >100%.Stage 4. The tert.-butyl2-(2-(4-methoxy-N,2,6-trimethylphenylsulfonamido)ethoxy)-acetate (17.95g, max. 42.6 mmole) was stirred in a solution of TFA (30 ml) and DCM(200 ml) for 2 hours at RT. After completion of the reaction the solventwas removed on a rotary evaporator and the remaining TFA was removed byevaporating twice with toluene and once with diisopropyl ether. Yield:13.6 g, 96% over 3 stages.

Preparation of{2-[methyl-(2,4,6-trimethyl-benzenesulfonyl)-amino]-ethoxy}acetic AcidS2

Stage 1. 2-(methylamino)ethanol (6.4 ml, 79.8 mmole) was dissolved inDMC (500 ml) and triethylamine (13.3 ml, 95.9 mmole) was added. Thesolution was cooled to 0° C. and a solution of2,3,6-trimethylbenzene-1-sulfonyl chloride (21 g, 95.9 mmole) dissolvedin DCM (65 ml) was added dropwise, and the whole was stirred for 4 hoursat RT. After completion of the reaction the reaction mixture was washedfirst with water and then with sodium carbonate solution, and the phaseswere separated and extracted three times with DCM. The combined organicphases were dried over Na₂SO₄ and concentrated by evaporation. The crudeproduct was purified by column chromatography (silica gel, diethylether/hexane 9:1).Stage 2. Tetra-n-butylammonium hydrogen sulfate (2.24 g, 6.6 mmole) wasadded to a solution ofN-(2-hydroxyethyl)-N,2,4,6-tetramethylbenzenesulfonamide (16.9 g, 66mmole) in toluene (450 ml) and cooled to 0° C. NaOH solution (50%, 445ml) was then added, followed by the dropwise addition of tert.-butylbromoacetate (20.3 ml, 138.5 mmole). The mixture was then stirred for3.5 hours at RT, following which the aqueous phase was separated andextracted twice with diethyl ether (450 ml). The combined organic phaseswere dried over Na₂SO₄, concentrated by evaporation in vacuo, and theresidue was purified by column chromatography on silica gel (ethylacetate). Yield: 15.2 g, 62%.Stage 3. Tert-butyl(2-(2-(N,2,4,6-tetramethylphenylsulfonamido)ethoxy)acetate (15.2 g, 41mmole) was stirred for 4 hours at RT in a solution of TFA (63 ml) andDCM (290 ml). After completion of the reaction the solvent was removedon a rotary evaporator and the remaining TFA was removed by evaporatingtwice with toluene (200 ml).

Preparation of{2][4-methoxy-2,3,6-trimethyl-benzenesulfonyl)-methyl-amino]-ethoxy}aceticAcid S3

Stage 1. A solution of 4-methoxy-2,3,6-trimethylbenzenesulfonyl chloride(2.29 g, 9.19 mmole) in THF (30 ml) was added dropwise at 0° C. to asolution of 2-methylaminoethanol (0.95 ml, 11.8 mmole) and triethylamine(5 ml) in THF (15 ml). The mixture was then stirred for 5 hours at RT,concentrated by evaporation in vacuo, and the residue was taken up inNaHCO₃ solution and extracted with ethyl acetate (3×30 ml). The combinedorganic phases were dried with Na₂SO₄ and concentrated by evaporation invacuo. Yield: 2.38 g, 90%.Stage 2. NaOH solution (35%, 40 ml) was added at 0° C. to a solution ofN-(2-hydroxyethyl)-4-methoxy-2,3,6,N-tetramethylbenzenesulfonamide (2.34g, 8.2 mmole) and tetra-n-butylammonium hydrogen sulfate (611 mg, 1.8mmole) in toluene (40 ml). A solution of tert.-butyl bromoacetate (1.82ml, 12.3 mmole) in toluene (35 ml) was then added dropwise to thevigorously stirred two-phase system. The mixture was then stirred for 2hours at RT, following which the aqueous phase was separated and theorganic phase was washed neutral with water (3×40 ml). The organic phasewas dried with Na₂SO₄, concentrated by evaporation in vacuo and theresidue was purified by flash chromatography with ethylacetate/cyclohexane (1:3). Yield: 2.50 g, 76%.Stage 3. Triethylsilane (1.54 ml, 9.6 mmole) followed by TFA (5 ml) wereadded to a solution of{2-[(4-methoxy-2,3,6-trimethylbenzenesulfonyl)-methylamino]-ethoxy}aceticacid tert-butyl acetate (2.48 g, 6.18 mmole) in DCM (50 ml), and thewhole was stirred for 5 hours at RT. The mixture was then concentratedby evaporation in vacuo and the residue was taken up several times intoluene and concentrated by evaporation each time. The crude product wasdissolved in ethyl acetate and extracted with 5% NaHCO₃ solution (3×50ml). The combined organic phases were adjusted to pH 1 with conc.hydrochloric acid and re-extracted with ethyl acetate (3×50 ml). Thecombined organic phases were dried with Na₂SO₄ and concentrated byevaporation in vacuo. Yield 2.41 g, >99%.

Preparation of{2-[benzyl-(4-methoxy-2,3,6-trimethyl-benzenesulfonyl)-amino]-ethoxy}aceticAcid S4

Stage 1. Triethylamine (11.2 ml, 80 mmole) was added to a solution of2-benzylaminoethanol (5.28 g, 35 mmole) in DCM (200 ml) and cooled usingan icebath. 4-methoxy-2,3,6-trimethylbenzene-1-sulfonyl chloride (7.9 g,32 mmole) was then added and stirred for 3 hours at RT. After addinghydrochloric acid (0.5 M, 100 ml) the organic phase was separated,washed with water, dried over Na₂SO₄, filtered, and the solvent wasdistilled off. The crude product was used without further purification.Stage 2. n-Bu₄NCl (2.78 g, 10 mmole) was added to a solution oftert.-butyl bromoacetate (6.5 ml, 45 mmole) in toluene (125 ml), cooledto 0° C., and then aqueous 35% NaOH (150 ml) was added followed by thedropwise addition ofN-benzyl-N-(2-hydroxyethyl)-4-methoxy-2,3,6-trimethylbenzenesulfonamide(10.8 g, 30 mmole) dissolved in toluene (25 ml). The reaction mixturewas stirred for 3 hours, then washed with water until neutral, driedwith Na₂SO₄, and the organic solvent was distilled off. The crudeproduct was used without further purification.Stage 3. The tert.-butyl2-(2-N-benzyl-4-methoxy-2,6-dimethylphenylsulfonamido)-ethoxy)acetate(14.3 g, 30 mmole) was dissolved in DCM (200 ml), TFA (30 ml) was added,and the reaction mixture was stirred for 2 hours at RT. The solvent waslargely distilled off. The residue was taken up in toluene (300 ml) andconcentrated by evaporation on a rotary evaporator. The crude productwas purified by washing with diisopropyl ether.

Preparation of{2-[benzyl-(4-methoxy-2,6-dimethyl-benzenesulfonyl)-amino]-ethoxy}aceticAcid S5

Stage 1. Triethylamine (11.2 ml, 80 mmole) was added to a solution of2-benzylaminoethanol (5.28 g, 35 mmole) in DCM (200 ml) and cooled usingan icebath. 4-methoxy-2,6-dimethylbenzene-1-sulfonyl chloride (7.5 g, 32mmole) was then added and stirred for 5 hours at RT. After addinghydrochloric acid (0.5 M, 100 ml) the organic phase was separated,washed with water, dried over Na₂SO₄, filtered, and the solvent wasdistilled off. The crude product was used without further purification.Stage 2. n-Bu₄NCl (2.78 g, 10 mmole) was added to a solution oftert.-butyl bromoacetate (6.5 ml, 45 mmole) in toluene (125 ml), cooledto 0° C., and aqueous 35% NaOH (150 ml) was first added, followed by thedropwise addition ofN-benzyl-N-(2-hydroxyethyl)-4-methoxy-2,6-dimethylbenzenesulfonamide(10.4 g, 30 mmole) dissolved in toluene (25 ml). The reaction mixturewas stirred for 3 hours, then washed with water till neutral, dried withNa₂SO₄, and the organic solvent was distilled off. The crude product wasused without further purification.Stage 3. The tert.-butyl2-(2-N-benzyl-4-methoxy-2,6-dimethylphenylsulfonamido)-ethoxy)acetate(19.4 g, 41.8 mmole) was dissolved in a mixture of methanol (150 ml),THF (165 ml) and aqueous NaOH solution (6 M, 150 ml, 900 mmole) andstirred for 1 hour at RT. After completion of the reaction the solutionwas concentrated and HCl (6 M, 155 ml) was added at 0° C. The aqueousphase was extracted with ethyl acetate (2×150 ml) and the combinedorganic phases were dried over Na₂SO₄ and concentrated. Yield: 17.05 g,100%.

Preparation of2-((4-methoxy-N,2,3,5-tetramethylphenylsulfonamido)-methoxy)acetic AcidS6

Stage 1. K₂CO₃ (102 g, 740 mmole) and methyl iodide (55.3 ml, 888 mmole)were added to a solution of 2,3,6-trimethylphenol (80.6 g, 740 mmole) inDMSO (90 ml) and stirred for 2 days at RT. The reaction mixture wasadded to water (750 ml) and extracted twice with heptane (500 ml and 300ml). The combined organic phases were washed with satd. NaCl solution,dried over Na₂SO₄, and concentrated. The residue was taken up inheptane, washed with KOH solution (2 M), dried over Na₂SO₄ andconcentrated. Yield: 76.26 g, 80%.Stage 2. A solution of 2-methoxy-1,3,4-trimethylbenzene (85.18 g, 532mmole) in DCM (500 ml) was cooled to 0° C. A solution of chlorosulfonicacid (38.9 ml, 585 mmole) was added dropwise to the solution and stirredovernight at RT. After completion of the reaction the reaction mixturewas concentrated. The residue was taken up in heptane and vigorouslystirred. The heptane was decanted and concentrated. Yield: 14.3 g, 11%.

The still remaining solids were taken up in DCM. The organic phase waswashed with water, dried over Na₂SO₄ and concentrated. A furtherfraction was obtained in a yield of 38.6 g, 29%.

Stage 3. 2-(methylamino)ethanol (5.57 ml, 69.0 mmole) was dissolved inDCM (100 ml) and triethylamine (20.2 ml, 144 mmole) was added. Thesolution was cooled to 0° C. and a solution of4-methoxy-2,3,5-trimethylbenzene-1-sulfonyl chloride (14.3 g, 57.5mmole) dissolved in DCM (100 ml) was added dropwise and stirred for 3hours at RT. After completion of the reaction HCl (0.5 M, 130 ml) wasadded, the phases were separated, washed with water, dried over Na₂SO₄and concentrated. The crude product was used without furtherpurification in the next stage. Yield: 15.69 g, 95%.Stage 4. Tetra-n-butylammonium chloride (5.06 g, 18.2 mmole) was addedto a solution ofN-(2-hydroxyethyl)-4-methoxy-N,2,3,5-tetramethylbenzenesulfonamide(15.69 g, 54.6 mmole) in toluene (300 ml) and cooled to 0° C. NaOHsolution (35%, 300 ml) was first of all added, followed by the dropwiseaddition of tert.-butyl bromoacetate (11.9 ml, 81.9 mmole). The mixturewas then stirred for 3.5 hours at RT, following which the aqueous phasewas separated and the organic phase was washed with water (3×300 ml)until neutral. The organic phase was dried with Na₂SO₄, concentrated byevaporation in vacuo, and the residue was purified by columnchromatography on silica gel (heptane/ethyl acetate 4:1→2:1). Yield:19.23 g, 88%.Stage 5. An NaOH solution (6 M, 200 ml, 1.2 mole) was added to anice-cooled solution of tert.-butyl2-(2-(4-methoxy-N,2,3,5-tetramethylphenylsulfonamido)ethoxy)-acetate(19.23 g, 47.89 mmole) in THF (100 ml) and methanol (100 ml) and stirredovernight at RT. The reaction solution was then acidified with HCl (6 M,250 ml) and extracted with DCM. The organic phase was washed withsaturated NaCl solution, dried over Na₂SO₄ and concentrated byevaporation. Yield: 16.58 g, 100%.

Preparation of2-(2-(N-isobutyl-4-methoxy-2,3,6-trimethylphenylsulfonamido)ethoxy)aceticAcid S7

Stage 1. Triethylamine (42.4 ml, 302 mmole) was added to a solution ofethanolamine (8.01 ml, 133 mmole) dissolved in DCM (200 ml). Thesolution was cooled on an ice bath and2,3,6-trimethyl-4-methoxybenzenesulfonyl chloride (30 g, 121 mmole)dissolved in DCM (200 ml) was added dropwise. The reaction mixture wasstirred overnight at RT. HCl solution (1 M, 125 ml) was then added, andthe organic phase was separated, washed with water, dried over Na₂SO₄and concentrated by evaporation to dryness. The crude product was usedwithout further purification in the next stage.Stage 2. K₂CO₃ (11.11 g, 80.4 mmole) and 1-bromo-2-methylpropane (43.7ml, 402 mmole) were added in succession to a solution ofN-(2-hydroxyethyl)-4-methoxy-2,3,6-trimethylbenzenesulfonamide (11 g,max. 38.69 mmole) in acetonitrile (400 ml) and heated overnight underreflux. Further 1-bromo-2-methylpropane (21.9 ml, 201 mmole) was addedand heating was continued overnight under reflux. After cooling to RT,the reaction mixture was first of all filtered through filter earth andthe filtrate was then concentrated by evaporation to dryness. The crudeproduct was purified by column chromatography (silica gel, heptane/ethylacetate 2:1). Yield: 8.30 g, 63% over 2 stages.Stage 3. n-Bu₄NCl (2.33 g, 8.4 mmole) was added to a solution ofN-(2-hydroxyethyl)-N-isobutyl-4-methoxy-2,3,6-trimethylbenzenesulfonamide(8.3 g, 25.19 mmole) in toluene (100 ml) and DCM (100 ml), cooled to 0°C., after which aqueous 35% NaOH (175 ml) was first of all added,followed by the dropwise addition of tert.-butyl bromoacetate (5.51 ml,37.8 mmole). The reaction solution was stirred for 3 hours at RT. Aftercompletion of the reaction the phases were first of all separated, thenwashed with water until neutral, dried with Na₂SO₄, and the organicsolvent was distilled off. The crude product was purified by columnchromatography (silica gel, heptane/ethyl acetate 4:1). Yield: 10.8 g,97%.Stage 4. The tert.-butyl2-(2-(N-isobutyl-4-methoxy-2,3,6-trimethylphenyl-sulfonamido)ethoxy)-acetate(10.8 g, 24.3 mmole) was dissolved in a mixture of methanol (100 ml),THF (100 ml) and aqueous NaOH solution (6 M, 100 ml, 600 mmole) andstirred for 1 hour at RT. After completion of the reaction the solutionwas concentrated and HCl (6 M, 125 ml) was added at 0° C. The aqueousphase was extracted with DCM (100 ml) and ethyl acetate (150 ml). Thecombined organic phases were dried over Na₂SO₄ and concentrated.Remaining impurities were removed by repeated dissolution in diisopropylether and diethyl ether, followed by evaporation. Yield: 9.36 g, 99%.

Preparation of 3-(naphthalene-2-sulfonamido)-3-phenylpropionic Acid S8

Stage 1. Thionyl chloride (19.1 g, 162 mmole) was added dropwise to asolution, cooled to 0° C., of 3-amino-3-phenylpropionic acid (8.9 g, 54mmole) in methanol (3 ml/mmole). The reaction mixture was then heatedfor 12 hours under reflux (DC check). The solvent was completely removedand the residue was dried in vacuo. The crude product was used withoutfurther purification in the next stage.Stage 2. Triethylamine (9.7 g, 96 mmole) was added to a solution, cooledto 0° C., of methyl 3-amino-3-phenylpropionate (5.73 g, 32 mmole) inDCM. Naphthalene-2-sulfonyl chloride (8.7 g, 38.4 mmole) dissolved inDCM (50 ml) was added to this reaction solution. The reaction mixturewas stirred for 3 hours at RT (DC check). After completion of thereaction the reaction mixture was diluted with DCM, washed with waterand satd. NaCl solution and dried over Na₂SO₄. The solvent was removedand the crude product was purified by column chromatography (silica gel,ethyl acetate/hexane 3:7).Stage 3. LiOH x H₂O (0.25 g, 18 mmole) was added at a reactiontemperature of 0° C. to a solution of methyl3-(naphthalene-2-sulfonamido)-3-phenylpropionate (3.3 g, 9 mmole) in amethanol/water mixture (3:1, 90 ml). The reaction mixture was stirredfor 16 hours at RT. The solvent was removed under reduced pressure, andthe residue was taken up in water and washed with DCM. The aqueous phasewas then carefully acidified with HCl (1 N) and extracted with ethylacetate. The organic phase was washed with water and satd. NaCl solutionand dried over Na₂SO₄. The product was obtained in sufficient purityafter removing the solvent.

Preparation of (R)-3-(Naphthalene-2-sulfonamido)-3-phenylpropanoic AcidS9

Procedure for Step-1:

To a solution of (R)-ethyl 3-amino-3-phenylpropanoate hydrochloride(5.04 g, 21.9 mmol) and naphthalene-2-sulfonyl chloride (4.97 g, 21.9mmol) in CH₂Cl₂ (60 mL) was added a solution of Et₃N (7.65 mL, 54.9mmol) in CH₂Cl₂ (60 mL) at 0° C. over a period of 45 min. The reactionmixture was stirred at room temperature for 42 h and then washed withaqueous 1 M HCl (300 mL). The organic layer was dried (Na₂SO₄) andevaporated to dryness, which gave 8.05 g (96%) of S9-1 as a light pinksolid.

Procedure for Step-2:

To a solution of sulfonamide S9-1 (7.82 g, 20.39 mmol) in THF (100 mL)and MeOH (100 mL) was added aqueous 4 M NaOH (15.35 mL, 61.4 mmol) andthe mixture was stirred at room temperature for 18 h. The reaction wasnot complete according to TLC. Therefore, more aqueous 4 M NaOH (6 mL,24 mmol) was added. After stirring for another 6 h the organic solventswere evaporated and aqueous 1 M HCl (100 mL) was added at 0° C. Theaqueous layer was then extracted with CH₂Cl₂ (100 mL); the organic layerwas dried (Na₂SO₄) and evaporated to dryness to afford carboxylic acidS9 (6.97 g, 96%).

The following amine building blocks were used for the synthesis of thesulfonamide compounds according to the invention:

Amine building block Structure Name A1 

1-ethyl-1,2,3,4- tetrahydropyrrolo[1,2]a]pyrazine A2 

1-(4-methoxyphenyl)-1,2,3,4- tetrahydropyrrolo[1,2]a]pyrazine A3 

1-phenyl-1,2,3,4- tetrahydropyrrolo[1,2]a]pyrazine A4 

1-(3,4-difluorophenyl)-1,2,3,4- tetrahydropyrrolo[1,2-a]pyrazine A5 

1-(3,4-dimethylphenyl)-1,2,3,4- tetrahydropyrrolo[1,2-a]pyrazine A6 

1-(3-fluorophenyl)-1,2,3,4- tetrahydropyrrolo[1,2-a]pyrazine A7 

1-(thiophen-2-yl)-1,2,3,4- tetrahydropyrrolo[1,2-a]pyrazine A8 

1-(3-(trifluoromethyl)-1,2,3,4- tetrahydropyrrolo[1,2-a]pyrazine A9 

1-(3-methoxyphenyl)-1,2,3,4- tetrahydropyrrolo[1,2-a]pyrazine A10

1-(2-fluoro-4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine A11

1-phenethyl-1,2,3,4-tetrahydropyrrolo[1,2- a]pyrazine A12

1-propyl-1,2,3,4-tetrahydropyrrolo[1,2- a]pyrazine A13

1-isopropyl-1,2,3,4-tetrahydropyrrolo[1,2- a]pyrazine A14

1-ethyl-6-methyl-1,2,3,4- tetrahydropyrrolo[1,2-a]pyrazine A15

1-isopropyl-6-methyl-1,2,3,4- tetrahydropyrrolo[1,2-a]pyrazine A16

1-tert-butyl-1,2,3,4-tetrahydropyrrolo[1,2- a]pyrazine A17

1-methyl-1,2,3,4-tetrahydropyrrolo[1,2- a]pyrazine A18

N,N-dimethyl-1-(1-phenyl-1,2,3,4- tetrahydropyrrolo[1,2-a]pyrazin-6-yl)methanamine A19

1-phenyl-6-(pyrrolodin-1-ylmethyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine A20

1-phenyl-6-(piperidin-1-ylmethyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine A21

4-((1-phenyl-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-6-yl)methyl)morpholine A22

1-(1-benzyl-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-6-yl)-N,N-dimethylmethanamine A23

N,N-dimethyl(1-phenethyl-1,2,3,4- tetrahydropyrrolo[1,2-a]pyrazin-6-yl)methanamine A24

1-(1-butyl-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-6-yl)-N,N-dimethylmethanamine A25

N,N-dimethyl(1-thiophen-2-yl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-6- yl)methanamine A26

1-(1-ethyl-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-6-yl)-N,N,-dimethylmethanamine A27

1-(pyridine-3-yl)-1,2,3,4- tetrahydropyrrolo[1,2-a]pyrazine A28

1-(6-chloropyridin-3-yl)-1,2,3,4- tetrahydropyrrolo[1,2-a]pyrazine A29

5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine A30

6-((4-methylpiperazin-1-yl)methyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine A31

4-((1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-6- yl)methyl)morpholine A32

6-(pyrrolidin-1-ylmethyl)-1,2,3,4- tetrahydropyrrolo[1,2-a]pyrazine A33

6-(3-(4-methylpiperazin-1-yl)propyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine A34

1-(4-tert-butylphenyl)-1,2,3,4- tetrahydropyrrolo[1,2-a]pyrazine A35

4-(2-(1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin- 6-yl)ethyl)morpholine A36

6-(2-(pyrrolidin-1-yl)ethyl)-1,2,3,4- tetrahydropyrrolo[1,2-a]pyrazineA37

6-(2-(4-methylpiperazin-1-yl)ethyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine A39

tert-Butyl 6-(pyridin-4-yl)-3,4- dihydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate A40

tert-Butyl 6-(pyridin-4-ylmethyl)-3,4-dihydropyrrolo[1,2-a]pyrazine-2(1H)- carboxylate A41

tert-Butyl 6-(2-(pyridin-4-yl)ethyl)-3,4-dihydropyrrolo[1,2-a]pyrazine-2(1H)- carboxylate A42

tert-Butyl 6-(pyridin-3-yl)-3,4- dihydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate A43

tert-Butyl 6-(pyridin-3-ylmethyl)-3,4-dihydropyrrolo[1,2-a]pyrazine-2(1H)- carboxylate A44

tert-Butyl 6-(2-(pyridin-3-yl)ethyl)-3,4-dihydropyrrolo[1,2-a]pyrazine-2(1H)- carboxylate A45

tert-Butyl 2-(pyridin-4-yl)-5,6- dihydroimidazo[1,2-a]pyrazine-7(8H)-carboxylate A46

tert-Butyl 2-(pyridin-4-ylmethyl)-5,6-dihydroimidazo[1,2-a]pyrazine-7(8H)- carboxylate A47

tert-Butyl 2-(2-(pyridin-4-yl)ethyl)-5,6-dihydroimidazo[1,2-a]pyrazine-7(8H)- carboxylate A48

3-(Piperidin-1-ylmethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine

Synthesis of the Amine Building Blocks A1-17, A27-28, A34

Stage 1. NaOH (9.4 g, 0.23 mole) and tetrabutylammonium hydrogen sulfate(0.8 g, 2.36 mmole) were added to a solution of the correspondingpyrrole (0.06 mmole) in acetonitrile (33 ml) and stirred for 30 minutesat RT. After the addition of 2-chloroethylamine hydrochloride (8.2 g,0.07 mole) the reaction mixture was heated for 24 hours under reflux.After the reaction mixture had cooled the insoluble inorganic residuewas filtered off and the solvent was removed under reduced pressure. Thecrude product was distilled in vacuo (35°-37° C., 0.037 mbar)

¹H NMR (400 MHz, CDCl₃) δ ppm 2.95-3.15 (m, 1H) 3.89-4.00 (m, 1H)6.12-6.21 (m, 1H) 6.64-6.73 (m, 1H)

Literature: Cuadro A. M., Matia M. P., Garcia J. L., Vaquero J. J. andAlvarez-Builla J.: Synth. Commun., 1991, 21(4), 535-544.Stage 2, Method A. A solution of the 2-(1H-pyrrol-1-yl)ethanamine (0.1mole) and the corresponding aldehyde (0.1 mole) in acetic acid (250 ml)was stirred for 48 hours at RT. After completion of the reaction thesolvent was removed on a rotary evaporator and the residue was taken upin aqueous sodium carbonate solution (10%) and extracted with DCM. Theorganic phase was then dried over MgSO₄ and concentrated by evaporationin vacuo. Purification was carried out by column chromatography onneutral Al₂O₃ or silica gel or by washing with 2-propanol or bycrystallising from ethanol or 2-propanol/n-hexane

Literature: I. Jirkovski, R. Baudy, Synthesis 1981, 481-483

Stage 2, Method B. Acetic acid (0.3 ml) was added to a solution of the2-(1H-pyrrol-1-yl)ethanamine (0.05 mole) and the corresponding aldehyde(0.05 mole) in ethanol (25 ml) and heated for 10 minutes under reflux.The reaction mixture was then stirred for a further hour at RT. Thereaction mixture was concentrated by evaporation on a rotary evaporatorand taken up in ethyl acetate. The organic phase was washed with NaHCO₃solution, dried over MgSO₄ and concentrated by evaporation. Purificationwas carried out if necessary by column chromatography on neutral Al₂O₃or silica gel.Stage 2, Method C. Benzotriazole (54.5 mmole) and a spatula tip amountof p-toluenesulfonic acid were added to a solution of the2-(1H-pyrrol-1-yl)ethanamine (54.5 mmole) and corresponding aldehyde(54.5 mmole) in toluene (500 ml). The reaction mixture was heatedovernight on a Dean-Stark water separator. After completion of thereaction first of all the solvent was removed on a rotary evaporator andthe residue was taken up in ethyl acetate. The organic phase was washedfirstly with 1 M NaOH and then with satd. NaCl solution. The organicphase was dried over Na₂SO₄ and then concentrated by evaporation todryness. Purification was carried out if necessary by columnchromatography by neutral Al₂O₃ or silica gel.

Stationary No. R¹ Method phase Solvent A1 Ethyl —* — — A24-methoxyphenyl —* — — A3 Phenyl A Al₂O₃ Gradient hexane → hexane: ethylacetate 8:2 A4 3,4-difluorophenyl B Al₂O₃ Gradient hexane → hexane:ethyl acetate 95:5 A5 3,4-dimethylphenyl B Al₂O₃ Gradient hexane →hexane: ethyl acetate 8:2 A6 3-fluorophenyl B —** — A7 2-thiophenyl BAl₂O₃ Hexane A8 3-(trifluoro-methyl)phenyl B —** — A9 3-methoxyphenyl B—** — A10 2-fluoro-4-(trifluoro- B Al₂O₃ Gradient hexane → methyl)phenylhexane: ethyl acetate 9:1 A11 Phenethyl B —** — A12 n-propyl —* — — A13Isopropyl —* — — A14 Ethyl —* — — A15 Isopropyl —* — — A16 t-butyl BSilica gel DCM: methanol 98:2 A17 Methyl B Silica gel DCM: methanol 9:1A27 3-pyridyl C Al₂O₃ Gradient hexane → hexane: ethyl acetate 7:3 →ethyl acetate A28 6-chloropyridin-3-yl B Al₂O₃ Gradient hexane → hexane:ethyl acetate 8:2 A34 4-tert-butylphenyl A —*** — *The amine iscommercially obtainable **The crude product was used without furtherpurification ***The crude product was recrystallised in ethanol.

5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine A29

Stage 1. A mixture of 2-aminopyrazin (25 g, 262.9 mmole),chloroacetaldehyde (50% in water, 50 ml, 394 mmole) and NaHCO₃ (33.1 g,394 mmole) was heated for 2 days at 100° C. The reaction mixture wasthen cooled to RT, satd. K₂CO₃ solution (100 ml) was added, and themixture was washed with DCM. The organic phase was dried over Na₂SO₄ andthen concentrated by evaporation to dryness. Purification was carriedout by column chromatography on silica gel (DCM/methanol, 95:5+5% NH₄OH[35%].Stage 2. The imidazo[1,2-a]pyrazine (7.2 g, 60.44 mmole) was dissolvedin 2-methoxyethanol (100 ml) and PtO₂ (1.2 g, 5.13 mmole) was added. Thereaction mixture was stirred overnight at RT in an autoclave under ahydrogen atmosphere (4 bar). The autoclave was then flushed withnitrogen, the reaction mixture was filtered through filter earth,concentrated, and the solvent residues were then extracted with toluene.Purification was carried out by column chromatography on silica gel(DCM/7 N NH₃ in methanol, 95:5)

Synthesis of the Amine Building Blocks A18-26, A30-A32 Synthesis of theAminals

Stage 1, Method A. The formaldehyde solution (37% in water, 119 ml, 1.6mole) was placed in a reaction vessel, dimethylamine solution (40% inwater, 405 ml, 3.2 mole) was added, and the mixture was then stirredovernight at RT. After completion of the reaction K₂CO₃ was added to thereaction mixture until phase separation occurred. The phases wereseparated and dried over K₂CO₃. The product was purified by means offractional distillation (b.p. 80-84° C.).

¹H NMR (300 MHz, CDCl₃) δ_(ppm) 2.23 (s, 12H) 2.73 (s, 2H).

Literature: M. Gaudry, Y. Jasor, B. T. Khac, Org. Synth. 59, 153-158Stage 1, Method B. The formaldehyde solution (37% in water, 59.5 ml, 0.8mole) was placed in a reaction vessel and the corresponding amine (1.6mole) was added. The mixture was then stirred overnight at RT. Thereaction mixture was worked up by adding water (100 ml) and wasextracted four times with 200 ml of ethyl acetate each time. Thecombined organic phases were dried over MgSO₄ and concentrated. Thecrude product could be used without further purification.Stage 2. A reaction flask was heated and the aminal (60 mmole) was addedand dissolved or suspended in diethyl ether (70 ml). Acetyl chloride (72mmole) dissolved in diethyl ether (20 ml) was added dropwise whilecooling with ice. The reaction mixture was then stirred overnight at RT.The precipitate that had formed was filtered off through a glass frit,quickly transferred to a round-bottomed flask and dried under an oilpump vacuum. The crude product was used without further purification.Literature: G. Kienast, L. F. Tietze, Angew. Chemie 1976, 88, 8, 261-262

Aminal preparation method (Stage NR²R³ Aminal name 1) Iminium salt nameNMe₂ N,N,N′,N′- A N-methyl-N- tetramethylmethanediaminemethylenemethaniminium chloride

Dipyrrolidin-1-ylmethane B 1-methylene-pyrrolidinium chloride

Dimorpholinomethane B 1-methylene-morpholinium chloride

Dipiperidin-1-ylmethane B 1-methylene-piperidinium chloride

Bis-(4-methylpiperazin-1- yl)methane B 4-methyl-1-methylene-piperazin-1-ium chloride

1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine

TFA (0.5 ml) was added to a solution of 1-(2-aminoethyl)pyrrole (9mmole) in ethanol (20 ml) and 37% formaldehyde (9 mmole). The reactionmixture was stirred for 15 minutes at 50° C. The reaction solution wasthen cooled to 25° C. and stirred for 4 hours at this temperature. Thereaction solution was concentrated by evaporation under reducedpressure. The residue was taken up in ethyl acetate and washed withaqueous sodium carbonate solution. The organic phase was separated,dried over Na₂SO₄ and concentrated by evaporation to dryness. Theproduct was used without further purification.

Aminoalkylation

Stage 1, Method A. The corresponding 1-substituted1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine (1 equiv.) was dissolved in 2.5ml/mmole DCM in a heated three-necked flask. Di-tert-butyl dicarbonate(0.5 equiv.) was dissolved in 1.5 ml/mmole DCM and added dropwise within30 minutes. The suspension was stirred overnight at RT. The reactionmixture was worked up by adding satd. sodium carbonate solution and theorganic phase was separated. The aqueous phase was then extracted twicewith DCM. The organic phases were combined, dried over magnesium sulfateand concentrated by evaporation. The products were purified by columnchromatography on silica gel.Stage 1, Method B. Diisopropylethylamine (12.15 mmole) and di-tert-butyldicarbonate (8.9 mmole) were added to a solution of the correspondingly1-substituted 1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine (8.1 mmole) inDCM. The reaction mixture was stirred for 16 hours at 25° C. The organicphase was then washed with sodium carbonate solution, water and satd.NaCl solution, dried over Na₂SO₄ and concentrated by evaporation. Thecrude product was purified by column chromatography (silica gel, ethylacetate/DCM, 99:1)

R¹ Method Name Ethyl A tert-butyl 1-ethyl-3,4-dihydropyrrolo[1,2-]]pyrazine- 2(1H)-carboxylate Butyl A tert-butyl1-butyl-3,4- dihydropyrrolo[1,2-a]pyrazine- 2(1H)-carboxylate Phenyl Atert-butyl-1-phenyl-3,4-dihydropyrrolo[1,2- a]pyrazine-2(1H)-carboxylateBenzyl A tert-butyl-1-benzyl-3,4-dihydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate Phenethyl A tert-butyl1-phenethyl-3,4-dihydroppyrrolo[1,2- a]pyrazine-2(1H)-carboxylate2-thiophenyl A tert-butyl-1-(thiophen-2-yl)- 3,4-dihydroppyrrolo[1,2-a]pyrazine-2(1H)-carboxylate H B tert-butyl 3,4-dihydroppyrrolo[1,2-a]pyrazine-2(1H)- carboxylate

Stage 2. Methods for the Aminoalkylation

Method A. The BOC-protected 1-substituted1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine (1 equiv.) was dissolved inacetonitrile (5 ml/mmole), the corresponding iminium salt (1 equiv.) wasadded and the reaction mixture was stirred overnight at RT. For theworking-up the reaction mixture was first adjusted to pH 1 with 1N HCland then extracted three times with diethyl ether. The aqueous phase wasthen made alkaline with sodium hydrogen carbonate solution and extractedthree times with diethyl ether. The combined organic phases were driedover magnesium sulfate and concentrated by evaporation on a rotaryevaporator. The crude product was purified if necessary by columnchromatography on silica gel (solvent: gradient: DCM/methanol99:1→95:5).Method B. The BOC-protected 1-substituted1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine (1 equiv.) was dissolved inacetonitrile (10 ml/mmole), the corresponding iminium salt (1 equiv.)was added, and the reaction mixture was stirred overnight at RT. For theworking-up the reaction mixture was diluted with ethyl acetate and thenwashed with sodium hydrogen carbonate solution, water and satd. NaClsolution, dried over Na₂SO₄ and concentrated by evaporation. The crudeproduct was purified by column chromatography (silica gel, DCM/methanol95:5)

Stage 3: Methods for Cleavage of the Protective Groups

Method A. The aminoalkylated Boc-protected 1-substituted1,2,3,4-tetrahydropyrrolo-[1,2-a]pyrazine was dissolved in DCM (7ml/mmole), TFA (10 equiv.) was added, and the reaction mixture wasstirred overnight at RT. After completion of the reaction (DC check) thereaction mixture was made alkaline with sodium carbonate solution. Thephases were separated and the aqueous phase was extracted three timeswith DCM. The combined organic phases were dried over magnesium sulfateand the solvent was removed on a rotary evaporator. The crude productcould be used without further purification.Method B. The aminoalkylated Boc-protected 1-substituted1,2,3,4-tetrahydropyrrolo-[1,2-a]pyrazine was dissolved in ethyl acetate(1 ml/mmole) and a satd. solution of HCl in ethyl acetate (3 ml/mmole)was added at 0° C. The reaction mixture was then heated to RT andstirred for 2 hours. The solvent was removed and the product was usedwithout further purification.

Method for Amino- removal of alkylation protective method groups No. R¹NR²R³ (Stage 2) (Stage 3) Name A18 Phenyl NMe₂ A AN,N-dimethyl-1-(1-phenyl-1,2,3,4- tetrahydropyrrolo[1,2-a]pyrazin-6-yl)methanamine A19 Phenyl

A A 1-phenyl-6-(pyrrolidin-1-ylmethyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine A20 Phenyl

A A 1-phenyl-6-(piperidin-1-ylmethyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine A21 Phenyl

A A 4-((1-phenyl-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-6-yl)methyl)morpholine A22 Benzyl NMe₂ A A1-(1-benzyl-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-6-yl)-N,N-dimethylmethanamine A23 Phenethyl NMe₂ A AN,N-dimethyl-1-(1-phenethyl-1,2,3,4- tetrahydropyrrolo[1,2-a]pyrazin-6-yl)methanamine A24 Butyl NMe₂ A A1-(1-butyl-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-6-yl)-N,N-dimethylmethanamine A25 2-thienyl NMe₂ A AN,N-dimethyl-1(1-(thiophen-2-yl)-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazin-6- yl)methanamine A26 Ethyl NMe₂ A A1-(1-ethyl-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-y-yl)-N,N-dimethylmethanamine A30 H

B B 6-((4-methylpiperazin-1-yl)methyl-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine A31 H

B B 4-((1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin- 6-yl)methyl)morpholineA32 H

B B 6-(pyrrolidin-1-ylmethyl)-1,2,3,4- tetrahydropyrrolo[1,2-a]pyrazine

Preparation of the Amine Building Blocks A33

Stage 1. A solution of oxalyl chloride (1 equiv.) in DCE (15 ml) wasadded to an ice-cooled solution of dry DCE (15 ml) and dry DMF (1equiv.) and stirred for 15 minutes at RT. The solution was re-cooled to0° C. and a solution of tert-butyl3,4-dihydropyrrolo-[1,2-]pyrazine-2(1H)-carboxylate (5 g, 22.25 mmole)in DCE (15 ml) was added. The reaction solution was stirred for 30minutes at this temperature (DC check). Ice was then added, followed byaqueous NaOH solution (50%). The aqueous phase was extracted with DCMand the organic phase was then washed in succession with water and satd.NaCl solution. After drying over Na₂SO₄, the solvent was removed in arotary evaporator. The resulting crude product was used without furtherpurification in the next stage.Stage 2. A solution of triethylphosphonium acetate (48.9 mmole) in dryTHF (160 ml) was slowly added to a suspension of NaH (60%, 48.9 mmole)in dry THF (160 ml), cooled to 0° C., and then stirred for 60 minutes at25° C. The reaction mixture was then cooled to 0° C. and the aldehyde(from Stage 1, 22.25 mmole) in dry THF (160 ml) was added dropwise, thetemperature being maintained constant. The reaction mixture was thenheated to 25° C. and stirred for 16 hours at this temperature until thereaction had gone to completion. The reaction mixture was hydrolysedfirst with ice and then with satd. NaCl solution. The aqueous phase wasextracted with ethyl acetate. The organic phase was then washed withwater and satd. NaCl solution. The organic phase was dried over Na₂SO₄and the solvent was removed on a rotary evaporator. The crude productwas purified by column chromatography on silica gel (solvent: DCM/ethylacetate, 95:5).Stage 3. A solution of the ester (from Stage 2, 9.37 mmole) in methanol(150 ml) was firstly deoxygenated with argon over a period of 15 minutesand Pd/C (10%, 20 wt. %) was added. The reaction mixture washydrogenolysed for 45 minutes under atmospheric pressure (LCMS check).After completion of the reaction the reaction mixture was filteredthrough filter earth and washed with methanol. The combined organicphases were concentrated and the resulting product was used withoutfurther purification in the next stage.Stage 4. DIBAL-H (1 equiv., 1.5 M in toluene) was added dropwise at −70°C. and under an argon atmosphere to a solution of the tert-butyl6-(2-ethoxycarbonylethyl)-3,4-dihydro-1H-pyrrolo[1,2-a]pyrazine-2-carbonate(from Stage 3, 1 equiv.) in dry toluene (7 ml/mmole). The reactionmixture was stirred for 1 hour at this temperature, after which theeduct had completely reacted (DC check). Methanol (30 ml) was added at−70° C. and the reaction mixture was heated to 25° C. Saturated NaClsolution (30 ml) was added. The reaction mixture was stirred for 30minutes at this temperature and then filtered through filter earth. Thereaction mixture was washed several times with ethyl acetate. Thecombined organic phases were washed with saturated NaCl solution andthen dried over Na₂SO₄, and the solvent was removed on a rotaryevaporator. The product obtained was used without further purificationin the next stage.Stage 5. The corresponding amine (1 equiv.) and glacial acetic acid (170μl/mmole) were added to a solution of the aldehyde (from Stage 4, 1.5equiv.) in DCM (20 ml/mmole) at 25° C. and stirred for 30 minutes atthis temperature. Sodium triacetoxy boron hydride (4 equiv.) was addedto the reaction mixture and stirred for 20 hours at 25° C. (DC check).The reaction mixture was then diluted with DCM and washed withsaturated, aqueous sodium hydrogen carbonate solution. The reactionmixture was dried over Na₂SO₄ and the solvent was removed on a rotaryevaporator. The crude product was purified by column chromatography onsilica gel (solvent: DCM/methanol, 9:1).

Preparation of the Amine Building Blocks A35 and A36

The synthesis of the aldehyde reacted in Stage 1 was carried outaccording to Stage 1 of the synthesis of the amine building block A33.

Stage 1. Ammonium acetate (0.45 equiv.) was added to a solution of thealdehyde (10.4 mmole) in nitromethane (14.5 ml). The reaction mixturewas then heated under reflux for 2 hours (DC check). After completion ofthe reaction the nitromethane was carefully removed under reducedpressure. The residue was taken up in ethyl acetate and washedsuccessively with water and saturated sodium chloride solution. Theorganic phase was dried over sodium sulfate and the solvent was removedon a rotary evaporator. The crude product was purified by columnchromatography on silica gel (solvent: hexane/ethyl acetate 9:1).Stage 2. The nitro compound from Stage 1 (32 mmole) was added to amixture of methanol and DMF (2:1, 17.5 ml/mmole) and cooled to 0° C.NaBH₄ (48 mmole) was added in portions to this mixture. The reactionmixture was stirred for 30 minutes at 0° C. (DC check). Water (14ml/mmole) and 1 drop of acetic acid were then added. The product wasextracted with DCM. The organic phase was washed with saturated sodiumchloride solution, dried over sodium sulfate, and the solvent wasremoved on a rotary evaporator. The crude product was purified by columnchromatography on silica gel (solvent: hexane/ethyl acetate 9:1).Stage 3. A solution of the nitro compound (3.5 g, 12 mmole) from Stage 2in ethanol (60 ml) was cooled to 0° C. and zinc dust (10 equiv.) wasadded in portions. The reaction mixture was stirred at 0° C. for 12hours and then filtered through celite. The filtrate was washed severaltimes with ethanol. The combined organic phases were concentrated byevaporation. The brown residue was taken up in DCM and washed insuccession with sodium carbonate solution and saturated sodium chloridesolution. The residue was then dried over sodium sulfate and the solventwas removed on a rotary evaporator. The crude product was used withoutfurther purification.Stage 4. Thetert-butyl-6-(2-aminoethyl)-3,4-dihydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate(1 equiv.) was dissolved in toluene (5 ml/mmole) and potassium carbonate(5 equiv.) was added. 1-chloro-2-(2-chloroethoxy)ethane or2-chloro-N-(2-chloroethyl)-N-methyl-methanamine (1.5 equiv.) was thenadded at RT. The reaction mixture was heated for 16 hours at 100° C. ina closed tube (DC check). After completion of the reaction the mixturewas cooled to RT, diluted with ethyl acetate, and washed in successionwith water and saturated sodium chloride solution. The organic phase wasdried over sodium sulfate and the solvent was removed on a rotaryevaporator. The crude product was purified by column chromatography onsilica gel (solvent: DCM/methanol, NRR′=morpholine: 98:2,NRR′=methylpiperazine: 94:6).

Preparation of the Amine Building Block A37

Stage 1. Butanediol (5 g, 56 mmole) was dissolved in DCM, triethylamine(280 mmole) was added and the mixture was cooled to 0° C.Methanesulfonic acid chloride (140 mmole) was added at this temperatureand stirred for 1 hour at 0° C. After completion of the reaction themixture was diluted with DCM and washed in succession with water andsaturated sodium chloride solution. The organic phase was dried oversodium sulfate and the solvent was removed on a rotary evaporator. Thecrude product was used without further purification.Stage 2. Thetert-butyl-6-(2-aminoethyl)-3,4-dihydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate(1 equiv.) was dissolved in toluene (5 ml/mmole) and potassium carbonate(5 equiv.) was added. Butane-1,4-diyldimethanesulfonate (1.5 equiv.) wasthen added at RT. The reaction mixture was heated for 16 hours at 100°C. in a closed tube (DC check). After completion of the reaction themixture was cooled to RT, diluted with ethyl acetate, and washed insuccession with water and saturated sodium chloride solution. Theorganic phase was dried over sodium sulfate and the solvent was removedon a rotary evaporator. The crude product was purified by columnchromatography on silica gel (solvent: DCM/methanol).

Preparation of the Amine Building Block A39 tert-Butyl6-(pyridin-4-yl)-3,4-dihydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate

Procedure for Step-1:

To a solution containing 4 g (0.06 mol) of pyrrole in 33 ml ofacetonitrile were added 9.4 g (0.23 mol) of powdered sodium hydroxideand 0.8 g (2.36 mmol) of tetrabutylammonium hydrogensulfate. After themixture was stirred at 25° C. for 30 minutes, 2-chloroethylaminehydrochloride (8.2 g, 0.07 mol) was added. The reaction mixture wasrefluxed for 24 hrs, inorganic solid was filtered off and the solventwas removed under reduced pressure to get crude 1-(2-aminoethyl)pyrrole.This was distilled under vacuum to get a colorless liquid that was usedin the next step directly. Yield: 30% (crude)

Procedure for Step-2:

To a ethanol solution (20 ml) of 1-(2-aminoethyl)pyrrole (9 mmol) and37% formaldehyde (9 mmol) was added TFA (0.5 ml) and the resultingreaction mixture was allowed to stir at 50° C. for 15 minutes. It wasthen cooled to come to 25° C. and stirred at this temperature for 4 hrs.Solvent was removed under reduced pressure, residue was dissolved inethyl acetate, basified with aqueous sodium carbonate solution, organiclayer was separated and dried over sodium sulfate. Evaporation of theorganic layer gave the crude 1,2,3,4-Tetrahydro-pyrrolo[1,2-a]pyrazinewhich was dissolved in dichloromethane (90 ml) at to it DIPEA (12.15mmol) and boc anhydride (8.9 mmol) were added at 0° C. The resultingreaction mixture was allowed to stir for 16 hrs at 25° C. Organic layerwas washed with sodium carbonate, water and brine and finally dried oversodium sulfate. Evaporation of the organic layer gave the crude productwhich was purified by column chromatography (1% ethyl acetate indichloromethane) or (10% ethyl acetate in hexane).

Procedure for Step-3:

To a solution of 3,4-Dihydro-1H-pyrrolo[1,2-a]pyrazine-2-carboxylic acidtert-butyl ester (200 mg, 0.9 mmol) obtained from step-2 in dry dimethylacetamide (200 μL) was added cesium acetate (3 eqv), diisopropyl amine(4 eqv) and 4-bromopyridine hydrochloride (2 eqv) under argonatmosphere. To this reaction mixture was then added Pd(OAc)₂ (0.15 eqv)under inert atmosphere and the reaction was heated at 130° C. for 16hrs. It was then diluted with ethyl acetate, filtered through celite bedand the organic layer was washed successively with water and brine.Evaporation of organic layer under reduced pressure gave the crudeproduct which was purified by column chromatography. Yield: 40%

Preparation of the Amine Building Block A40: tert-Butyl6-(pyridin-4-ylmethyl)-3,4-dihydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate

Procedure for Step-1:

Compound A (3 g, 13.5 mmol) was taken in dry toluene (30 ml) and to itwas added zinc dust (3 eqv) under inert atmosphere. The resultingreaction mixture was stirred at 25° C. for 5 minutes and thenisonicotinoyl chloride hydrochloride (1.5 eqv) was added under stirring.Stirring was continued for further 16 hrs. Reaction mixture was filteredthrough celite bed, diluted with ethyl acetate, organic layer was washedsuccessively with water and brine and finally dried over sodium sulfate.Evaporation of organic layer under reduced pressure gave the crudeproduct that was purified by column chromatography (5% methanol indichloromethane) Yield: 40%

Procedure for Step-2:

A 2:1 mixture of AcOH-MeOH (36 ml) was added to the keto compound (3.6mmol) and to it zinc dust (50 eqv) was added under stirring. Theresulting reaction mixture was allowed to stir at 25° C. for 16 hrs(monitored by LCMS) and filtered through celite bed. Solvent wascompletely evaporated, residue was taken in ethyl acetate, organic layerwas washed successively with sodium bicarbonate and brine and finallydried over sodium sulfate. Evaporation of organic layer under reducedpressure gave the crude product which was purified by columnchromatography (5% methanol in dichloromethane). Yield: 26%

Preparation of the amine building block A41: tert-Butyl6-(2-(pyridin-4-yl)ethyl)-3,4-dihydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate

Procedure for Step-1:

To an ice cold solution of dry DCE (15 ml) and dry DMF (1 eqv) was addeda solution of oxalyl chloride (1 eqv) in dry DCE (15 ml) and theresulting reaction mixture was stirred at 25° C. for 15 minutes.Reaction was again cooled to 0° C. and to it was added a solution of3,4-Dihydro-1H-pyrrolo[1,2-a]pyrazine-2-carboxylic acid tert-butyl ester(5 gm, 22.25 mmol) in dry DCE (15 ml) and the reaction was stirred atthe same temperature for 30 minutes (monitored by TLC). It was quenchedwith ice, 50% aqueous NaOH solution was then added, aqueous layer wasextracted with DCM and the organic layer was washed successively withwater and brine. After drying over sodium sulfate, organic layer wasevaporated under reduced pressure to get the crude product which wasused immediately in the next step without any further purification.Yield: 60% (crude)

Procedure for Step-2:

To a solution of 4-picoline (4 mmol) in dry THF (10 ml) was added n-BuLi(1.57M, 2.5 ml, 4 mmol) at −78° C. and the resulting reaction mixturewas allowed to stir at 25° C. for 1 hr. It was again cooled to 0° C. andthe aldehyde obtained from step-1 (1 g, 4 mmol) was added to thereaction mixture drop wise. After stirring at 25° C. for 3 hrs, reactionmixture was quenched with water (5 ml), extracted with ethyl acetate andthe combined organic layer was washed with brine. After drying oversodium sulfate, organic layer was evaporated under reduced pressure toget the crude alcohol that was purified by column chromatography (2%methanol in dichloromethane). Yield: 48%

Procedure for Step-3:

To a solution of the alcohol obtained from step-2 (1 g, 2.91 mmol) inxylene (15 ml) wadded p-toluene sulfonic acid (0.05 eqv) and theresulting reaction mixture was refluxed using a dean-stark apparatus for5 hrs (monitored by TLC). Reaction mixture was cooled to roomtemperature, diluted with ethyl acetate and washed successively withsaturated sodium bicarbonate solution, water and brine. Organic layerwas dried over sodium sulfate evaporated under reduced pressure to getthe crude product that was purified by column chromatography (2%methanol in dichloromethane). Yield: 56%

Procedure for Step-4:

A solution of the compound obtained from step-3 was taken in methanol(15 ml) and deoxygenated with argon. To it was added 10% Pd—C (150 mg)and the resulting reaction mixture was hydrogenated under atmosphericpressure for 3 hrs. It was filtered through celite bed, residue washedwith methanol and the combined organic layer was evaporated to drynessto get the crude product which was used directly in the next stepwithout any further purification. Yield: 80% (crude)

Preparation of the Amine Building Block A42 tert-Butyl6-(pyridin-3-yl)-3,4-dihydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate

Procedure:

To a solution of 3,4-Dihydro-1H-pyrrolo[1,2-a]pyrazine-2-carboxylic acidtert-butyl ester (2 g, 9 mmol) in dry dimethyl acetamide (2 ml) wasadded cesium acetate (3 eqv), diisopropyl amine (4 eqv) and3-bromopyridine (2 eqv) under argon atmosphere. To this reaction mixturewas then added Pd(OAc)₂ (0.15 eqv) under inert atmosphere and thereaction was heated at 130° C. for 16 hrs. It was then diluted withethyl acetate, filtered through celite bed and the organic layer waswashed successively with water and brine. Evaporation of organic layerunder reduced pressure gave the crude product that was purified bycolumn chromatography. Yield: 40%

Preparation of the Amine Building Block A43: tert-Butyl6-(pyridin-3-ylmethyl)-3,4-dihydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate

Procedure for Step-1: Same as step-1 of A41

Procedure for Step-2:

To a solution of n-BuLi (1.57 M, 2.54 ml, 4 mmol) in dry ether (5 ml) at−78° C. was added 3-bromo pyridine (4 mmol) and the reaction mixture wasallowed to stir at the same temperature for 30 minutes. To it aldehyde(4 mmol) obtained from step-1 in dry ether (10 ml) was added drop wiseand the resulting reaction mixture was allowed to stir at 25° C. for 16hrs (monitored by TLC). Reaction was quenched with water, extracted withethyl acetate, combined organic layer was washed with brine and finallydried over sodium sulfate. Evaporation of organic layer under reducedpressure gave the crude product which was purified by columnchromatography (3% methanol in dichlormethane). Yield: 30%

Procedure for Step-3:

A 2:1 mixture of AcOH-MeOH (16 ml) was added to the keto compound (3.6mmol) and to it zinc dust (50 eqv) was added under stirring. Theresulting reaction mixture was allowed to stir at 25° C. for 16 hrs(monitored by LCMS) and filtered through celite bed. Solvent wascompletely evaporated, residue was taken in ethyl acetate, organic layerwas washed successively with sodium bicarbonate and brine and finallydried over sodium sulfate. Evaporation of organic layer under reducedpressure gave the crude product that was purified by columnchromatography (5% methanol in dichloromethane). Yield: 35%

Preparation of the Amine Building Block A44: tert-Butyl6-(2-(pyridin-3-yl)ethyl)-3,4-dihydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate

Procedure for Step-1: Same as step-1 of A41

Procedure for Step-2:

To an ice cold suspension of the wittig salt (4 mmol) in dry THF (25 ml)was slowly added n-BuLi (5 mmol) and the resulting reaction mixture wasallowed to stir at that temperature for 30 minutes. To it aldehyde B (2mmol) in dry THF (10 ml) was added at 0° C. and allowed to stir forfurther 1 hr. Reaction was quenched with saturated ammonium chloridesolution and extracted with ethyl acetate. Organic layer was washed withwater and brine and finally dried over sodium sulfate. Evaporation oforganic layer under reduced pressure gave the crude product that wasunstable and used immediately without any further purification.

Procedure for Step-3:

To a DMA solution (2 ml) of the crude compound obtained from step-2(9.12 mmol) was added cesium acetate (3 eqv), diisopropyl amine (4 eqv)and 3-bromopyridine (2 eqv) under argon atmosphere. To this reactionmixture was then added Pd(OAc)₂ (0.15 eqv) under inert atmosphere andthe reaction was heated at 130° C. for 16 hrs. It was then diluted withethyl acetate, filtered through celite bed and the organic layer waswashed successively with water and brine. Evaporation of organic layerunder reduced pressure gave the crude product that was purified bycolumn chromatography (5% methanol in dichloromethane). Yield: 15%

Procedure for Step-4:

A solution of the compound obtained from step-3 (400 mg) was taken inmethanol (10 ml) and deoxygenated with argon. To it was added 10% Pd—C(200 mg) and the resulting reaction mixture was hydrogenated underatmospheric pressure for 3 hrs. It was filtered through celite bed,residue washed with methanol and the combined organic layer wasevaporated to dryness to get the crude product which was used directlyin the next step without any further purification. Yield: 80% (crude)

Preparation of the Amine Building Block A45 tert-Butyl2-(pyridin-4-yl)-5,6-dihydroimidazo[1,2-a]pyrazine-7(8H)-carboxylate

Procedure for Step-1:

To a solution of 2-aminopyrazine (1.87 g) in dry acetone (30 ml) wasadded potassium carbonate (3 eqv), 4-bromoacetyl pyridine (2 eqv) andthe resulting reaction mixture was heated at 60° C. for 20 hrs. Reactionmixture was filtered through a celite bed, residue washed with DCM andcombined organic layer was evaporated completely to get a brown residue.It was again dissolved in ethyl acetate, washed with water and brine andfinally dried over sodium sulfate. Evaporation of organic layer gave thecrude product which was purified by column chromatography (1% methanolin dichloromethane). Yield: 12%, 30% Starting material recovered.

Procedure for Step-2:

To a dry dioxane solution (22 ml) of the compound obtained from step-1(2.55 mmol) was added lithium borohydride (2 eqv) portion wise at 25° C.and the resulting reaction mixture was stirred at this temperature for10 minutes. It was then warmed to 60° C. and kept at that temperaturefor 30 minutes (monitored by TLC). Reaction was cooled to 0° C. andacidified with 1(N)HCl. Dioaxane was completely evaporated,dichloromethane (5 ml), diisopropyl ethyl amine (2.5 eqv) andboc-anhydride (1.5 eqv) was added to the residue and the resultingreaction mixture was allowed to stir at 25° C. for 16 hrs. It wasdiluted with dichloromethane, organic layer was washed with water andbrine and finally dried over sodium sulfate. Evaporation of the organiclayer gave the crude product which was purified by column chromatography(5% methanol in dichloromethane). Yield: 58%

Preparation of the Amine Building Block A46: tert-Butyl2-(pyridin-4-ylmethyl)-5,6-dihydroimidazo[1,2-a]pyrazine-7(8H)-carboxylate

Procedure for Step-1:

To a THF solution (40 ml) of Diisopropyl amine (4.46 ml, 1.5 eqv) wasadded BuLi (1.88 M, 1.5 eqv) at −15° C. and the resulting reactionmixture was allowed to stir at same temperature for 20 minutes. It wasthen cooled to −78° C. and 2-chloro-3-iodopyridine (5 g, 20.92 mmol) inTHF (10 ml) was added dropwise at the same temperature and allowed tostir for 1 hr at −78° C. Reaction was quenched with water (10 ml),stirred at ambient temperature for 15 minutes and extracted with ethylacetate. Organic layer was washed successively with brine and finallydried over sodium sulfate. Evaporation of organic layer under reducedpressure gave the crude product which was immediately used in the nextstep without any further purification. Yield: 80% (Crude)

Procedure for Step-2:

To a solution of 2-amino pyrazine (20 g, 210 mmol) in dimethoxy ethane(400 ml) was added ethyl bromopyruvate (32.8 ml) at 25° C. and theresulting reaction mixture was allowed to stir at the same temperaturefor 4 hrs. It was then cooled to 0° C. and stirred for 30 minutes. Theseparated solid was filtered and washed with ether. Solid residue wastaken in ethanol (1000 ml) and refluxed for 4 hrs. Solvent was removedcompletely, residue taken in chloroform (1000 ml), saturated sodiumbicarbonate solution (700 ml) was added to it and the mixture wasallowed to stir for 45 minutes. The mixture was filtered through celitebed, washed several times with chloroform and filtrate was dried oversodium sulfate. Evaporation of the organic layer under reduced pressuregave the crude mass, which was purified by crystallization usingether-methanol mixture.

Yield: 20%

Procedure for Step-3:

To a well stirred suspension of the ester obtained from step-1 (10 g,52.3 mmol) in dioxane (400 ml) was added lithium borohydride (2 eqv) at25° C. and the resulting reaction mixture was allowed to stir at thesame temperature for 10 minutes. It was then warmed to 60° C. and keptat this temperature for 20 minutes (! Higher temperature and morereaction time reduce the yield and quality of reaction). Reactionmixture was then cooled to 0° C., acidified with 1N HCl and dioxane wascompletely evaporated under reduced pressure. Residue was taken indichloromethane (200 ml), TEA (4eqv) and Boc-anhydride (1.2 eqv) wasadded to it and the resulting reaction mixture was allowed to stir at25° C. for 16 hrs. Organic layer was washed with water and brine andfinally dried over sodium sulfate. Evaporation of organic layer gave thecrude product which was purified by column chromatography (70% ethylacetate in hexane). Yield: 27%

Procedure for Step-4:

To a solution of the boc-ester (1 g, 3.38 mmol) obtained from step-3 indry toluene (40 ml) was added DIBAL (1M, 3.7 mmol) at −78° C. and thereaction mixture was allowed to stir at this temperature for 5 hrs(monitored by TLC). Reaction was quenched with methanol (3.7 ml) and wasslowly brought to 25° C. Brine (10 ml) was added to it and filteredthrough celite bed. Residue was washed with dichloromethane and combinedorganic layer was evaporated to get the crude aldehyde, which was useddirectly in the next step without any further purification. Yield: 800mg (crude)

Procedure for Step-5:

To a ether solution (17 ml) of 2-chloro-4-iodo pyridine (1 eqv) wasadded BuLi (1.2 eqv) at −78° C. and the resulting reaction mixture wasallowed to stir at the same temperature for 1 hr. To it was added thealdehyde (1 eqv) obtained from step-4 at −78° C. and stirred for 1 hr atthe same temperature. It was quenched with water, extracted with ethylacetate and the organic layer was washed successively with brine andfinally dried over sodium sulfate. Evaporation of organic layer underreduced pressure gave the crude product which was purified by columnchromatography. Yield: 35%

Procedure for Step-6:

A solution of the compound obtained from step-5 was taken in methanol(10 ml/mmol) and deoxygenated with argon. To it was added 10% Pd—C (50%by wt of the alcohol) and the resulting reaction mixture washydrogenated under atmospheric pressure for 16 hrs. It was then filteredthrough celite bed, residue washed with methanol and the combinedorganic layer was evaporated to dryness to get the crude product whichwas used directly in the next step without any further purification.Yield: 44% (crude)

Procedure for Step-7:

To a solution of the alcohol (1 eqv) obtained from step-6 in methanol (5ml/mmol) was added glacial acetic acid (10 ml/mmol), Zn dust (50 eqv)and the resulting reaction mixture was allowed to stir at ambienttemperature for 16 hrs. Reaction mixture was filtered through celitebed, washed with methanol and combined organic layer was evaporatedcompletely. It was then taken in ethyl acetate, washed with sodiumbicarbonate, water and brine and finally dried over sodium sulfate.Evaporation of organic layer under reduced pressure gave the crudeproduct which was purified by column chromatography (2% methanol indichloromethane). Yield: 26%

Preparation of the Amine Building Block A47: tert-Butyl2-(2-(pyridin-4-yl)ethyl)-5,6-dihydroimidazo[1,2-a]pyrazine-7(8H)-carboxylate

Procedure for Step-1:

To a solution of 2-amino pyrazine (20 g, 210 mmol) in dimethoxy ethane(400 ml) was added ethyl bromopyruvate (32.8 ml) at 25° C. and theresulting reaction mixture was allowed to stir at the same temperaturefor 4 hrs. It was then cooled to 0° C. and stirred for 30 minutes. Theseparated solid was filtered and washed with ether. Solid residue wastaken in ethanol (1000 ml) and refluxed for 4 hrs. Solvent was removedcompletely, residue taken in chloroform (1000 ml), saturated sodiumbicarbonate solution (700 ml) was added to it and the mixture wasallowed to stir for 45 minutes. The mixture was filtered through celitebed, washed several times with chloroform and filtrate was dried oversodium sulfate. Evaporation of the organic layer under reduced pressuregave the crude mass, which was purified by crystallization usingether-methanol mixture. Yield: 20%

Procedure for Step-2:

To a well stirred suspension of the ester obtained from step-1 (10 g,52.3 mmol) in dioxane (400 ml) was added lithium borohydride (2 eqv) at25° C. and the resulting reaction mixture was allowed to stir at thesame temperature for 10 minutes. It was then warmed to 60° C. and keptat this temperature for 20 minutes (! Higher temperature and morereaction time reduce the yield and quality of reaction). Reactionmixture was then cooled to 0° C., acidified with 1N HCl and dioxane wascompletely evaporated under reduced pressure. Residue was taken indichloromethane (200 ml), TEA (4eqv) and Boc-anhydride (1.2 eqv) wasadded to it and the resulting reaction mixture was allowed to stir at25° C. for 16 hrs. Organic layer was washed with water and brine andfinally dried over sodium sulfate. Evaporation of organic layer gave thecrude product which was purified by column chromatography (70% ethylacetate in hexane). Yield: 27%

Procedure for Step-3:

To a solution of the boc-ester (1 g, 3.38 mmol) obtained from step-2 indry DCM (40 ml) was added DIBAL (1M, 3.7 mmol) at −78° C. and thereaction mixture was allowed to stir at this temperature for 5 hrs(monitored by TLC). Reaction was quenched with methanol (3.7 ml) and wasslowly brought to 25° C. Brine (10 ml) was added to it and filteredthrough celite bed. Residue was washed with dichloromethane and combinedorganic layer was evaporated to get the crude aldehyde, which was useddirectly in the next step without any further purification. Yield: 800mg (crude)

Procedure for Step-4:

To a solution of 4-picoline (3 mmol) in dry THF (10 ml) was added n-BuLi(1.57M, 3 mmol) at −78° C. and the resulting reaction mixture wasallowed to stir at 25° C. for 1 hr. It was again cooled to 0° C. and thealdehyde obtained from step-3 (3 mmol) was added to the reaction mixturedrop wise. After stirring at 25° C., reaction mixture was quenched withwater (5 ml), extracted with ethyl acetate and the combined organiclayer was washed with brine. After drying over sodium sulfate, organiclayer was evaporated under reduced pressure to get the crude alcoholthat was purified by column chromatography (3% methanol indichloromethane). Yield: 36%

Procedure for Step-5:

To a solution of the alcohol obtained from step-4 (2.3 mmol) in xylene(12 ml) wadded p-toluene sulfonic acid (0.05 eqv) and the resultingreaction mixture was refluxed using a dean-stark apparatus for 5 hrs(monitored by TLC). Reaction mixture was cooled to room temperature,diluted with ethyl acetate and washed successively with saturated sodiumbicarbonate solution, water and brine. Organic layer was dried oversodium sulfate evaporated under reduced pressure to get the crudeproduct that was purified by column chromatography (2% methanol indichloromethane). Yield: 59%

Procedure for Step-6:

A solution of the compound (1.38 mmol) obtained from step-5 was taken inmethanol (15 ml) and deoxygenated with argon. To it was added 10% Pd—C(225 mg) and the resulting reaction mixture was hydrogenated underatmospheric pressure for 3 hrs. It was filtered through celite bed,residue washed with methanol and the combined organic layer wasevaporated to dryness to get the crude product which was used directlyin the next step without any further purification. Yield: 80% (crude)

Preparation of the Amine Building Block A483-(Piperidin-1-ylmethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine

Procedure for Step-1:

To a solution of 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinehydrochloride (1.0 g, 6.23 mmol) in CH₂Cl₂ (25 mL) were added Et₃N (2.17mL, 15.57 mmol) and Boc₂O (1.52 mL, 6.54 mmol) and the reaction wasstirred at room temperature overnight. The mixture was extracted withaqueous 0.25 M KHSO₄ (50 mL). The organic layer was dried (Na₂SO₄) andevaporated to dryness to afford compound A48-1 (1.29 g, 92%).

Procedure for Step-2:

To a solution of compound A48-1 (1.29 g, 5.75 mmol) in dry THF (50 mL)was added a solution of 2.5 M n-BuLi in hexane (2.53 mL, 6.33 mmol) at−78° C. under argon. After 15 min ethyl formate (702 μL, 8.63 mmol) wasadded and the reaction mixture was stirred for 15 min at −78° C.Saturated aqueous NH₄Cl (150 mL) was added and the mixture was extractedwith CH₂Cl₂ (3×100 mL). The combined organic layer was dried (Na₂SO₄)and evaporated to dryness to afford aldehyde A48-2 (1.21 g, 83%).

Procedure for Step-3:

To a solution of aldehyde A48-2 (1.21 g, 4.80 mmol), piperidine (522 μL,5.28 mmol) and AcOH (329 μL, 5.76 mmol) in CH₂Cl₂ (50 mL) was addedNaBH(OAc)₃ (1.53 g, 7.19 mmol) and the reaction mixture was stirred atroom temperature overnight. The mixture was diluted with CH₂Cl₂ (50 mL)and washed with brine (50 mL). The organic layer was dried (Na₂SO₄) andevaporated to dryness to afford amine A48-3 (1.53 g, 99%).

Procedure for Step-4:

To a solution of compound A48-3 (1.53 g, 4.76 mmol) in CH₂Cl₂ (30 mL)was added TFA (18.3 mL, 238 mmol) and the mixture was stirred at roomtemperature overnight. The mixture was concentrated in vacuo andco-evaporated twice with CH₂Cl₂ (50 mL) to afford amine A48 (3.18 g,‘302%’).

General Process for Preparing Substituted Sulfonamide Compounds of theInvention:

The carboxylic acids N are converted in an amide formation process usingprimary or secondary amines O in the presence of water-removing agentssuch as sodium or magnesium sulfate, phosphorus oxide or reagents suchas for example CDI, DCC (optionally polymer-bound), TBTU, EDCI, PyBOP orPFPTFA also in the presence of HOAt or HOBt and an organic base, forexample DIPEA or pyridine in an organic solvent such as THF,dichloromethane, diethyl ether, dioxane, DMF or acetonitrile, attemperatures from 0° C. to the reflux temperature, to yield the finalproducts corresponding to formula P.

Parallel Synthesis Methods Parallel Synthesis Method 1

Acid solution (0.05 M in DCM, 2 ml) was added to 105 μmole of CDIsolution (0.105 M in DCM, 1 ml) and shaken for 1 hour at RT. 100 μmoleof the amine solution (0.1 M in DCM) were then added at RT and shakenfor a further 12 hours at RT. 3 ml of water were next added to thereaction mixture, shaken for 15 minutes, and the organic phase wasseparated. After distilling of the solvent the crude products wereanalysed by means of LC-MS and purified by HPLC.

Parallel Synthesis Method 2

EDCI (1.5 equiv.), HOBt (1 equiv.) and diisopropylethylamine (1.5equiv.) were first of all added to a solution of the corresponding acid(1 equiv.) in DCM (3 ml/mmole) and stirred for 15 minutes at 25° C. Thecorresponding amine was dissolved in DCM (1 ml/mmole) in anotherreaction vessel, cooled to 0° C., and diisopropylethylamine (4 equiv.)was added. The cooled solution was added to the acid solution andstirred for 16 hours at RT. For working-up, the mixture was first of alldiluted with DCM and then washed in succession with ammonium chloridesolution, sodium carbonate solution and saturated NaCl solution, anddried over Na₂SO₄. The solution was concentrated by evaporation todryness. The product was purified using a purification system fromBiotage operating in parallel.

Parallel Synthesis Method 3

Stage 1. TFA (20% in DCM, 3 ml/mole) was added at 0° C. to theBoc-protected amine (1 equiv.). The reaction mixture was heated to 25°C. and stirred at this temperature for 2 hours (DC check). The solventwas completely removed and the product was carefully dried in order toremove traces of TFA. The crude product was used without furtherpurification.Stage 2. EDCI (1.5 equiv.), HOBt (1 equiv.) and DIPEA (2.5 equiv.) wereadded to a solution of the acid building block (1 equiv.) in DCM (3ml/mmole) and stirred for 15 minutes at 25° C. The Boc-deprotected amine(1.5 equiv.) in DCM (1 ml/mmole) was cooled to 0° C. in another reactionvessel and DIPEA (4 equiv.) was added. The solution thereby obtained wasadded to the solution of the acid building block. The reaction mixturewas stirred for 16 hours at 25° C. and then diluted with DCM. Theorganic phase was washed in succession with aqueous ammonium chloridesolution, aqueous sodium hydrogen carbonate solution and saturated NaClsolution. The organic phase was dried over Na₂SO₄ and concentrated byevaporation. The crude product was purified using a parallelpurification system from Biotage.

Biotage Purification of Library Compounds

-   Step-1: Before purification all the crude compounds were analyzed to    get LCMS data of each compound. Thus, it is possible to determine    the polarity of compounds.-   Step-2: Each compound was dissolved in minimum quantity of    dichloromethane and loaded onto a Biotage column (Biotage Si 12+M)    and it was then placed in the 12 channel Biotage Quad-3 parallel    purification system. At a time 12 compounds were purified.-   Step-3: Depending on the polarity of the compound (TLC was used to    determine the eluent) specific solvent mixtures were run in 12    channel Biotage Quad-3 purification system and the fractions were    collected in test tubes. Pure fractions were combined after checking    the TLC of all the fractions.-   Step-4: Combined pure fractions from each column were evaporated    under reduced pressure, transferred to pre-tared glass vials using    acetonitrile as solvent and dried in Speed Vac Thermo explorer to    get dry pure compound. These were then submitted for final analysis.

LCMS Method for Monitoring 1. LC Parameters

Column=phenomenex GEMINI 5 μm C18 110A (50*4.6 mm)U.V wavelength=220 nm, 260 nmShimadzu LC system injection volume=1.00 to 5.00 μl

(Depending on Concentration)

Flow rate=1.2 ml/min

Time Program:

A: 0.05% TFA (pH 2.3)

B: Acetonitrile

TIME MODULE EVENTS PARAMETER 0.01 Pumps % B 10 1.50 Pumps % B 30 3.00Pumps % B 90 4.00 Pumps % B 90 5.00 Pumps % B 10 5.10 System ControllerStop

2. MS Parameters Scan Type: Q1 MS (Q1) Polarity: Positive Scan ModeProfile Ion Source Turbo Spray

Source Temperature (at setpoint): 200° C.

Start Stop Time (amu) (amu) (sec) Param Start Stop 100.00 800.00 2.00CEP 26.51 41.21

Detector Parameters): IS (Ion Spray Voltage): 5500 Detector CEM: 2200.0DP (Declustering Potential): 50.00 EP (Entrance Potential): 10.00

HPLC: Schimadzu Prominance integrated with MS of API 2000 LCMS/MS ofApplied Biosystems, and ELS Detector of Polymer labs (temperature 50°C.)

Example 1N-(2-(2-(6-((dimethylamino)methyl)-1-phenyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,3,6-tetramethylbenzeneSulfonamide

CDl (0.2 g, 1.23 mmole) was first added to a solution S3 (0.41 g, 1.18mmole) in DCM (10 ml) and stirred for 1 hour at RT. The amine A18 (0.3G, 1.18 mmole) dissolved in DCM (10 ml) was then added at thistemperature and stirred for a further 16 hours at RT. After completionof the reaction the mixture was first washed with NH₄Cl solution andthen with saturated sodium carbonate solution. The organic phase wasdried over Na₂SO₄, filtered, and the solvent was distilled off. Thecrude product was purified by column chromatography (silica gel,DCM/methanol 98:2). m/z=582.3

Example 3N-(2-(2-(5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,6-trimethylbenzenesulfonamide

Stage 1. Oxalyl chloride (3.89 ml, 45.3 mmole) and 2 drops of DMF wereadded to a solution of the acid S1 (5.0 g, 15.1 mmole) in DCM (100 ml).The reaction mixture was stirred overnight at RT. After completion ofthe reaction the solvent was evaporated to dryness on a rotaryevaporator. The residue was taken up in DCM and again evaporated todryness. This was repeated a further two times. The crude product wasused without further purification. Yield: 5.18 g, 98%.Stage 2. Triethylamine (720 μl, 5.18 mmole) and5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride (238 mg,1.48 mmole) were added to a solution of the acid chloride (518 mg, 1.48mmole) in DCM (10 ml). The reaction mixture was stirred overnight at RT.After completion of the reaction the solvent was removed. Purificationwas first carried out by column chromatography (silica gel, DCM→DCM/7 MNH₃ in MeOH, 98:2). The product obtained was taken up in DCM and washedwith aqueous HCl (0.5 M, 10 ml). The organic phase was dried over Na₂SO₄and concentrated by evaporation. Yield: 210 mg, 32%. m/z=437.2

Preparation of2-(piperidin-1-ylmethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine

Stage 1. DMAP (0.75 g, 6.12 mmole) followed by Boc₂O (1.34 g, 6.12mmole) were added to a solution of the ethyl5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-2-carboxylate hydrochloride(1.09 g, 4.70 mmole) in DCM (100 ml). The reaction mixture was stirredfor 18 hours at RT. Since the reaction had still not gone to completion,further Boc₂O (0.12 g, 0.53 mmole) was added and the mixture was againstirred overnight. After completion of the reaction the reaction mixturewas washed with aqueous HCl solution 1 M, 100 ml), and the organic phasewas dried over Na₂SO₄ concentrated by evaporation in vacuo. The crudeproduct was purified by column chromatography (silica gel, ethylacetate) (Yield: 300 mg, 21%).Stage 2. A solution of 7-tert-butyl2-ethyl-5,6-dihydroimidazo[1,2-a]pyrazin-2,7(8H)-dicarboxylate (300 mg,1.02 mmole) in THF (15 ml) was cooled to −78° C. and DIBAL-H (1 M inhexane, 2.0 ml, 2.0 mmole) was slowly added under a N₂ atmosphere. Thereaction mixture was stirred for 1 hour at this temperature andNa₂SO₄×10 H₂O was then added until the evolution of gas was no longerobserved. Further Na₂SO₄×10 H₂O was added, filtered, and the residue waswashed with DCM (25 ml). The filtrate was concentrated and the crudeproduct obtained (450 mg) was used without further purification in thenext stage.Stage 3. The tert-butyl2-formyl-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-carboxylate (400 mg,max. 0.91 mmole) and piperidine (158 μl, 1.59 mmole) were dissolved inDCM (8 ml) and NaBH(OAc)₃ (506 mg, 2.39 mmole) was added in portions.The reaction mixture was stirred for 2 hours at RT and then hydrolysedwith satd. sodium hydrogen carbonate solution (25 ml). The phases wereseparated and the aqueous phase was extracted again with DCM (25 ml).The combined organic phases were washed with satd. NaCl solution, driedover Na₂SO₄, and concentrated by evaporation in vacuo (Yield: 260 mg,90% over 2 stages).Stage 4. TFA (2.83 ml, 36.7 mmole) was added to a solution of thetert-butyl2-(piperidin-1-ylmethyl)-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-carboxylate(235 mg, 0.73 mmole) in DCM (10 ml) and stirred for 3-4 hours at RT (DCcheck). After completion of the reaction the solvent was first of allremoved, DCM was added, and the reaction mixture was again concentratedby evaporation to dryness. The product was used without furtherpurification for further reactions.

Example 4(R)—N-(3-oxo-1-phenyl-3-(2-piperidin-1-ylmethyl)-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)propyl)naphthalene-2-sulfonamide

The acid S8 (274 mg, 0.77 mmole) and the amine (0.73 mmole) weredissolved in DCM and cooled to 0° C. HOAt (10.01 mg, 0.07 mmole)diisopropylethylamine (0.64 ml, 3.68 mmole) and EDCI (155 mg, 0.81mmole) were added at this temperature. The reaction mixture was stirredovernight at RT. After completion of the reaction (DC check) the mixturewas diluted with DCM (15 ml) and the organic phase was washed insuccession with aqueous KHSO₄ solution (0.5 M, 25 ml), satd. NaHCO₃solution (25 ml) and satd. NaCl solution (25 ml). The organic phase wasthen dried over Na₂SO₄ and concentrated. The crude product was purifiedby column chromatography (firstly silica gel, DCM/7 M NH₃ in MeOH, 9:1,then silica gel, DCM/7 M NH₃ in MeOH, 98:2→9:1). Yield: 105 mg.m/z=557.3

Example 2 Preparation of4-methoxy-N,2,6-trimethyl-N-(2-(2-oxo-2-(2-piperidin-1-ylmethyl)-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)ethoxy)ethyl)benzenesulfonamideHydrochloride

The acid S1 (1.68 g, 5.06 mmol), HOAt (69 mg, 0.51 mmole), DIPEA (5.30ml, 30.4 mmole) and EDCI (1.46 g, 7.59 mmole) were added to a solutionof the amine (3.17 g, max. 3.48 mmole) in DCM (50 ml). The reactionmixture was stirred overnight at RT. The mixture was then concentratedby evaporation to dryness. The crude product was purified by columnchromatography on silica gel (DCM/7 M NH₃ in methanol, 95:5). Theproduct obtained was taken up in DCM (25 ml) and washed with aqueous HCl(0.1 M, 20 ml). The organic phase was dried over Na₂SO₄ andconcentrated. Yield: 210 mg, 11%

Preparation of3-chloro-2-(piperidin-1-ylmethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine

Stage 1. Triethylamine (1.34 ml, 9.58 mmole) and Boc₂O (0.92 g, 4.22mmole) were added to a solution of theethyl-3-chloro-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-2-carboxylatehydrochloride (1.02 g, 3.83 mmole) in DCM (100 ml) and stirred for 18hours at RT. After completion of the reaction (DC check) the reactionmixture was diluted with DCM and washed with aqueous 0.5 M KHSO₄solution (100 ml). The organic phase was dried over Na₂SO₄ and thesolvent was evaporated after filtration.Stage 2. A solution of the Boc-protectedethyl-3-chloro-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-2-carboxylate(1.19 g, 3.62 mmole) in THF (25 ml) was cooled to −78° C. and DIBAL-H (1M in hexane, 7.24 ml, 7.24 mmole) was slowly added under a N₂atmosphere. The reaction mixture was stirred for 1 hour at −78° C. andhydrolysed with Na₂SO₄×10 H₂O until the evolution of gas was no longerobserved. An excess of Na₂SO₄×10 H₂O was added and the mixture was thenfiltered. The solid was washed with DCM (2×25 ml) and the filtrate wasthen concentrated by evaporation to dryness. The crude product obtainedwas used further without further purification.Stage 3. The aldehyde (720 mg, 2.52 mmole) and piperidine (249 μl, 2.52mmole) were dissolved in DCM (15 ml) and sodium triacetoxy boron hydride(822 mg, 3.88 mmole) was added in portions. The reaction mixture wasstirred for 4 hours at RT (LCMS check). The reaction mixture washydrolysed with saturated aqueous sodium hydrogen carbonate solution.The phases were separated and the aqueous phase was extracted once morewith DCM (25 ml). The combined organic phases were washed with saturatedNaCl solution (25 ml), dried over Na₂SO₄, and concentrated byevaporation to dryness.Stage 4. TFA (2.61 ml, 33.8 mmole) was added to a solution of theBoc-protected amine (240 mg, 0.68 mmole) in DCM (10 ml) and stirred for4 hours at RT. After completion of the reaction (DC check) the reactionmixture was concentrated by evaporation to dryness, taken up in DCM (20ml), concentrated by evaporation to dryness, taken up again in DCM (20ml) and then concentrated by evaporation to dryness. The crude productwas used further without further purification.

Example 5 Preparation of(R)—N-(3-(3-chloro-2-(piperidin-1-ylmethyl)-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)-3-oxo-1-phenylpropyl)naphthalene-2-sulfonamide

The acid S8 (264 mg, 0.74 mmole) was dissolved in DCM (10 ml), DIPEA(1.18 ml, 6.75 mmole) was added, and the mixture was cooled to 0° C.HATU (282 mg, 0.74 mmole) and the amine (crude product, max. 0.68 mmole)were added and the mixture stirred overnight at RT (DC check). Thereaction mixture was concentrated by evaporation to dryness, and thecrude product was purified by column chromatography on silica gel (DCM/7M NH₃ in methanol, 95:5). The product was taken up in DCM (10 ml) andwashed with aqueous NaHCO₃ solution. The organic phase was dried overNa₂SO₄ and concentrated. The product was re-purified via a flash column(silica gel, DCM/methanol, 9:1) Yield: 88 mg, 22% over 2 stages)

Example 6 Preparation ofN-(2-2-(3-chloro-2-(piperidin-1-ylmethyl)-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,6-trimethylbenzenesulfonamide

The acid S1 (218 mg, 657 μmole), HOAt (8.9 mg, 66 μmole) DIPEA (573 μl,3.28 mmole) and EDCI (189 mg, 985 μmole) were added to a solution of theamine (695 mg, max. 722 μmole) in DCM (25 ml) and stirred overnight atRT. The reaction mixture was then concentrated by evaporation to drynessand purified by column chromatography on silica gel (flash, DCM/7 M NH₃in methanol, 99:1). Yield: 319 mg, 86% over 2 stages.

Example No. 162N-((1R)-3-(1-Ethyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-3-oxo-1-phenylpropyl)naphthalene-2-sulfonamide

Carboxylic acid S9 (120 mg, 0.338 mmol) and N-ethyl-N′-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI) (96 mg, 0.507 mmol) weredissolved in CH₂Cl₂ (8 mL). HOBt (49 mg, 0.372 mmol),1-ethyl-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine (76 mg, 0.507 mmol) andDIPEA (146 μL, 0.845 mmol) were added and the mixture allowed to stirovernight at room temperature. The reaction mixture was diluted withsat. sodium hydrogen carbonate solution and the aqueous layer extractedwith CH₂Cl₂ (2×). The combined organics layers were dried (MgSO₄) andconcentrated in vacuo. The crude product was purified by columnchromatography (silica, ethylacetate/hexane, 2:1) to afford screeningcompound 162 (150 mg, 91%).

LC/MS: R_(t)=5.2 min; m/z=488.2 [MH]⁺

Example No. 1634-Methoxy-N,2,6-trimethyl-N-(2-(2-oxo-2-(3-(piperidin-1-ylmethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)ethoxy)ethyl)benzenesulfonamide

To a solution of amine A48 (795 mg, max. 1.19 mmol), carboxylic acid S1(394 mg, 1.19 mmol) and DIPEA (1.66 mL, 9.52 mmol) in CH₂Cl₂ (20 mL) wasadded HATU (498 mg, 1.31 mmol) and the mixture was stirred overnight atroom temperature. The mixture was evaporated to dryness and subjected tocolumn chromatography (flash, silica, CH₂Cl₂/(7 M NH₃ in MeOH), 99:1 to97:3). The product was then purified further by preparative LCMS twiceto afford screening compound 163 (35 mg, 5.5%).

Example No. 164(R)—N-(3-oxo-1-phenyl-3-(3-(piperidin-1-ylmethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)propyl)naphthalene-2-sulfonamide

To a solution of amine A48 (1.59 g, max 2.38 mmol), carboxylic acid S9(846 mg, 2.38 mmol) and DIPEA (3.32 mL, 19.0 mmol) in CH₂Cl₂ (40 mL) wasadded HATU (995 mg, 2.62 mmol) and the mixture was stirred overnight atroom temperature. The mixture was evaporated to dryness and subjected tocolumn chromatography (flash, silica, CH₂Cl₂/(7 M NH₃ in MeOH), 99:1 to97:3). The product was then purified further by preparative LCMS twiceto afford screening compound 164 (28 mg, 2.1%).

The synthesis methods (parallel syntheses) for the example compounds arelisted in the following table. The synthesised example compounds (1) to(161) were analysed inter alia according to their molecular weight. Themolecular weights measured by means of ESI-MS are summarised in thefollowing table:

Mol. wt. Example Method (ESI-MS) 1 582.3 2 533.3 3 537.2 4 556.3 5 591.26 567.2 7 2 534.3 8 2 542.2 9 2 547.28 10 2 558.23 11 2 518.26 12 3575.77 13 3 599.8 14 1 568.3 15 1 594.3 16 1 608.3 17 1 574.2 18 1 547.319 1 568.3 20 1 602.2 21 1 492.2 22 1 597.3 23 1 567.3 24 1 585.3 25 1573.2 26 1 597.3 27 1 505.3 28 1 463.2 29 1 526.2 30 1 560.2 31 1 555.232 1 525.2 33 1 561.2 34 1 553.3 35 1 543.2 36 1 531.2 37 1 593.2 38 1555.2 39 1 611.2 40 1 539.3 41 1 602.3 42 1 636.2 43 1 526.2 44 1 567.345 1 525.2 46 1 512.2 47 1 617.3 48 1 587.3 49 1 615.3 50 1 593.2 51 1643.3 52 1 491.3 53 1 449.2 54 1 512.2 55 1 546.2 56 1 436.2 57 1 547.258 1 539.3 59 1 529.2 60 1 517.2 61 1 579.2 62 1 541.2 63 1 597.2 64 1567.3 65 1 475.3 66 1 433.2 67 1 496.2 68 1 530.2 69 1 525.2 70 1 495.271 1 531.2 72 1 523.3 73 1 513.2 74 1 501.2 75 1 563.2 76 1 525.2 77 1581.2 78 1 551.3 79 1 505.3 80 1 463.2 81 1 526.2 82 1 560.2 83 1 555.284 1 525.2 85 1 561.2 86 1 553.3 87 1 543.2 88 1 531.2 89 1 555.2 90 1581.3 91 1 624.3 92 1 650.4 93 1 664.4 94 1 666.4 95 1 638.4 96 1 652.497 1 604.4 98 1 630.3 99 1 576.3 100 1 519.3 101 1 533.3 102 1 533.3 1031 533.3 104 1 547.3 105 1 582.3 106 1 608.3 107 1 622.3 108 1 624.3 1091 596.3 110 1 610.3 111 1 562.3 112 1 588.2 113 1 534.3 114 1 477.2 1151 491.3 116 1 684.3 117 1 700.3 118 1 672.3 119 1 686.4 120 1 638.4 1211 664.3 122 1 610.3 123 1 567.3 124 1 567.3 125 1 615.3 126 1 644.3 1271 670.3 128 1 684.3 129 1 658.3 130 1 650.3 131 1 596.3 132 1 539.3 1331 539.3 134 1 548.3 135 1 463.2 136 1 477.2 137 1 477.2 138 1 477.2 1391 552.3 140 1 578.3 141 1 592.3 142 1 594.3 143 1 566.3 144 1 558.2 1451 504.3 146 1 461.2 147 1 461.2 148 1 553.3 149 1 622.3 150 1 624.3 1511 596.3 152 1 477.2 153 1 491.3 154 1 553.3 155 1 553.3 156 584.3 157571.3 158 532.3 159 555.3 160 561.3 161 548.3

Parallel Synthesis Method 4:

Procedure for step-1: Boc-protected amine BB (1 eqv) was treated with20% TFA in DCM (10 ml/mol) at 0° C. and the resulting reaction mixturewas allowed to stir at 25° C. for 4 hrs (monitored by TLC). Solvent wascompletely evaporated, dried properly to remove traces of TFA and theresidue was directly used in library synthesis.Procedure for step-2: To a dichloromethane solution (3 ml/mmol) of acidBBs (1 eqv) was added EDCI (1.5 eqv), HOBT (1 eqv), DIPEA (2.5 eqv) andthe resulting reaction mixture was allowed to stir for 15 minutes at 25°C. In another R.B flask, Boc deprotected amine BB (1.5 eqv) indichloromethane (1 ml/mmol) was cooled in ice bath, treated with DIPEA(4 eqv) and it was added to the reaction mixture. Reaction mixture wasallowed to stir at 25° C. for 16 hrs and diluted with dichloromethane.Organic layer was successively washed with aqueous ammonium chloride,sodium bicarbonate and brine and finally dried over sodium sulfate.Evaporation of organic layer under reduced pressure gave the crudeproduct, which was purified by Biotage parallel purification system.Yield: 20-25%Example compounds 165-179 were Obtained by Parallel Synthesis Method 4:

Example No. Structure Name 165

4-Methoxy-N,2,6-trimethyl-N-(2-(2- oxo-2-(6-(pyridin-4-ylmethyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)- yl)ethoxy)ethyl)benzenesulfonamide166

4-Methoxy-N,2,6-trimethyl-N-(2-(2- oxo-2-(6-(pyridin-3-yl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)- yl)ethoxy)ethyl)benzenesulfonamide167

N-(3-Oxo-1-phenyl-3-(6-(pyridin-3- yl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)- yl)propyl)naphthalene-2-sulfonamide 168

N-(3-Oxo-1-phenyl-3-(6-(pyridin-4- yl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)- yl)propyl)naphthalene-2-sulfonamide 169

N-(3-Oxo-1-phenyl-3-(6-(pyridin-4- ylmethyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)- yl)propyl)naphthalene-2-sulfonamide 170

4-Methoxy-N,2,6-trimethyl-N-(2-(2- oxo-2-(6-(2-(pyridin-3-yl)ethyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)- yl)ethoxy)ethyl)benzenesulfonamide171

N-(3-Oxo-1-phenyl-3-(6-(2-(pyridin- 3-yl)ethyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)- yl)propyl)naphthalene-2-sulfonamide 172

4-Methoxy-N,2,6-trimethyl-N-(2-(2- oxo-2-(6-(2-(pyridin-4-yl)ethyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)- yl)ethoxy)ethyl)benzenesulfonamide173

N-(3-Oxo-1-phenyl-3-(6-(2-(pyridin- 4-yl)ethyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)- yl)propyl)naphthalene-2-sulfonamide 174

4-Methoxy-N,2,6-trimethyl-N-(2-(2- oxo-2-(6-(pyridin-3-ylmethyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)- yl)ethoxy)ethyl)benzenesulfonamide175

4-Methoxy-N,2,6-trimethyl-N-(2-(2- oxo-2-(2-(pyridin-4-yl)-5,6-dihydro-imidazo[1,2-a]pyrazin-7(8H)- yl)ethoxy)ethyl)benzenesulfonamide 176

N-(3-Oxo-1-phenyl-3-(6-(pyridin-3- ylmethyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)- yl)propyl)naphthalene-2-sulfonamide 177

4-Methoxy-N,2,6-trimethyl-N-(2-(2- oxo-2-(6-(pyridin-4-yl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)- yl)ethoxy)ethyl)benzenesulfonamide178

4-Methoxy-N,2,6-trimethyl-N-(2-(2- oxo-2-(2-(2-(pyridin-4-yl)ethyl)-5,6-dihydroimidazo[1,2-a]pyrazin- 7(8H)- yl)ethoxy)ethyl)benzenesulfonamide179

4-Methoxy-N,2,6-trimethyl-N-(2-(2- oxo-2-(2-(pyridin-4-ylmethyl)-5,6-dihydroimidazo[1,2-a]pyrazin- 7(8H)- yl)ethoxy)ethyl)benzenesulfonamideThe following building blocks were used in the synthesis of examplecompounds 165-179

Example Amine No. No. Amine Name Acid No. Acid Name 165 A406-(Pyridin-4-ylmethyl)- S1 2-(2-(4-Methoxy-N,2,6- 1,2,3,4-tetrahydro-trimethylphenylsulfonamido)ethoxy)acetic pyrrolo[1,2-a]pyrazine acid 166A42 6-(Pyridin-3-yl)-1,2,3,4- S1 2-(2-(4-Methoxy-N,2,6-tetrahydropyrrolo[1,2- trimethylphenylsulfonamido)ethoxy)acetica]pyrazine acid 167 A42 6-(Pyridin-3-yl)-1,2,3,4- S8 3-(Naphthalene-2-tetrahydropyrrolo[1,2- sulfonamido)-3- a]pyrazine phenylpropanoic acid168 A39 6-(Pyridin-4-yl)-1,2,3,4- S8 3-(Naphthalene-2-tetrahydropyrrolo[1,2- sulfonamido)-3- a]pyrazine phenylpropanoic acid169 A40 6-(Pyridin-4-ylmethyl)- S8 3-(Naphthalene-2- 1,2,3,4-tetrahydro-sulfonamido)-3- pyrrolo[1,2-a]pyrazine phenylpropanoic acid 170 A446-(2-(Pyridin-3-yl)ethyl)- S1 2-(2-(4-Methoxy-N,2,6- 1,2,3,4-tetrahydro-trimethylphenylsulfonamido)ethoxy)acetic pyrrolo[1,2-a]pyrazine acid 171A44 6-(2-(Pyridin-3-yl)ethyl)- S8 3-(Naphthalene-2- 1,2,3,4-tetrahydro-sulfonamido)-3- pyrrolo[1,2-a]pyrazine phenylpropanoic acid 172 A416-(2-(Pyridin-4-yl)ethyl)- S1 2-(2-(4-Methoxy-N,2,6- 1,2,3,4-tetrahydro-trimethylphenylsulfonamido)ethoxy)acetic pyrrolo[1,2-a]pyrazine acid 173A41 6-(2-(Pyridin-4-yl)ethyl)- S8 3-(Naphthalene-2- 1,2,3,4-tetrahydro-sulfonamido)-3- pyrrolo[1,2-a]pyrazine phenylpropanoic acid 174 A436-(Pyridin-3-ylmethyl)- S1 2-(2-(4-Methoxy-N,2,6- 1,2,3,4-tetrahydro-trimethylphenylsulfonamido)ethoxy)acetic pyrrolo[1,2-a]pyrazine acid 175A45 2-(Pyridin-4-yl)-5,6,7,8- S1 2-(2-(4-Methoxy-N,2,6-tetrahydroimidazo[1,2- trimethylphenylsulfonamido)ethoxy)acetica]pyrazine acid 176 A43 6-(Pyridin-3-ylmethyl)- S8 3-(Naphthalene-2-1,2,3,4-tetrahydro- sulfonamido)-3- pyrrolo[1,2-a]pyrazinephenylpropanoic acid 177 A39 6-(Pyridin-4-yl)-1,2,3,4- S12-(2-(4-Methoxy-N,2,6- tetrahydropyrrolo[1,2-trimethylphenylsulfonamido)ethoxy)acetic a]pyrazine acid 178 A472-(2-(Pyridin-4-yl)ethyl)- S1 2-(2-(4-Methoxy-N,2,6- 5,6,7,8-tetrahydro-trimethylphenylsulfonamido)ethoxy)acetic imidazo[1,2-a]pyrazine acid 179A46 2-(Pyridin-4-ylmethyl)- S1 2-(2-(4-Methoxy-N,2,6-5,6,7,8-tetrahydro- trimethylphenylsulfonamido)ethoxy)aceticimidazo[1,2-a]pyrazine acidThe purity (determined by UV), the ESI-MS Results as well as theretention times are given in the following table:

Purity-UV Example No. [%] MS-Found Rt [min] 165 100.0 527.3 2.791 166100.0 513.3 2.826 167 100.0 537.3 2.953 168 91.6 537.2 9.649 169 100.0551.3 2.904 170 100.0 541.2 2.829 171 100.0 565.1 2.938 172 97.2 541.12.824 173 100.0 565.4 9.877 174 99.3 527.5 2.823 175 100.0 514.4 2.683176 95.7 551.3 9.820 177 100.0 513.2 2.791 178 94.2 542.1 2.330 179 98.9528.2 2.280

Pharmacological Data:

The agonistic and antagonistic action of the compounds according to theinvention on the bradykinin 1 receptor (B1R) of humans and rats weredetermined as described above. Antagonists lead to a suppression of theCa²⁺ inflow. The % inhibition compared to the maximum achievableinhibition was calculated. The compounds according to the invention arehighly effective on the human and rat receptor.

hB1R rB1R [10 μM] [10 μM] % Example % Inhibition Inhibition 1 89 58 2106 104 3 43 93 4 102 98 5 99 97 6 100 99 7 101 99 8 95 42 9 101 102 1097 100 11 103 102 12 97 100 13 44 100 14 103 100 15 101 101 16 104 10217 102 102 18 82 98 19 101 98 20 84 98 21 31 100 22 53 97 23 47 97 24 3299 25 55 98 26 34 99 27 95 98 28 37 81 29 96 79 30 98 76 31 95 67 32 7899 33 71 66 34 58 42 35 81 48 36 97 85 37 38 72 38 97 43 39 35 80 40 3495 41 57 96 42 33 91 43 33 73 44 88 98 45 83 99 46 41 96 47 42 100 48 5498 49 39 69 50 48 100 51 58 85 52 100 98 53 101 99 54 98 93 55 100 99 5685 97 57 102 99 58 102 97 59 95 99 60 100 98 61 100 99 62 101 98 63 102100 64 100 99 65 101 99 66 87 92 67 99 100 68 101 100 69 101 100 70 10199 71 95 95 72 97 71 73 102 99 74 99 102 75 63 48 76 101 97 77 71 53 7832 77 79 101 100 80 99 97 81 98 99 82 101 99 83 101 100 84 101 99 85 9992 86 91 71 87 101 100 88 101 98 89 100 98 90 47 66 91 103 103 92 102102 93 103 102 94 104 102 95 101 101 96 102 101 97 89 102 98 101 102 99102 101 100 98 103 101 91 102 102 96 102 103 101 102 104 93 102 105 100100 106 99 101 107 98 102 108 102 102 109 102 101 110 103 100 111 100100 112 101 101 113 103 93 114 80 42 115 91 97 116 103 102 117 82 88 11896 96 119 52 54 120 84 92 121 101 102 122 101 101 123 41 86 124 58 96125 25 78 126 101 102 127 99 102 128 101 103 129 100 101 130 104 102 131101 101 132 100 102 133 105 102 134 104 103 135 104 102 136 104 103 137104 102 138 104 102 139 102 103 140 102 101 141 103 101 142 103 101 143100 99 144 104 104 145 104 103 146 102 102 147 103 103 148 100 98 149104 104 150 103 103 151 102 103 152 102 102 153 103 103 154 23 87 155 75101 162 57 98 163 103 164 102 165 100 99 166 100 99 167 32 70 168 55 57169 78 98 170 99 98 171 30 99 172 100 97 173 20 75 174 100 94 175 100102 176 45 87 177 99 97 178 99 100 179 100 100

The foregoing description and examples have been set forth merely toillustrate the invention and are not intended to be limiting. Sincemodifications of the described embodiments incorporating the spirit andsubstance of the invention may occur to persons skilled in the art, theinvention should be construed broadly to include all variation withinthe scope of the appended claims and equivalents thereof.

1. A substituted sulfonamide compound corresponding to formula I

wherein m and n each independently denote 0, 1 or 2; p denotes 1 or 2; Qdenotes —O— or —CH₂—; X denotes N or CR⁵; Y denotes N or CR⁶; Z denotesN or CR⁷; R¹ denotes aryl, heteroaryl, or an aryl or heteroaryl groupbonded via a C₁₋₆-alkylene group; R² and R³ each independently denote H,C₁₋₆-alkyl, aryl, heteroaryl, or an aryl or heteroaryl group bonded viaa C₁₋₆-alkylene group, C₂₋₆-alkenylene group or C₂₋₆-alkynylene group;R⁴ denotes H, halogen, CN, NO₂, C₁₋₆-alkyl, aryl, heteroaryl, or an arylor heteroaryl group bonded via a C₁₋₆-alkylene group, C₂₋₆-alkenylenegroup or C₂₋₆-alkynylene group; R⁵, R⁶ and R⁷ each independently denoteH, halogen, CN, C₁₋₆-alkyl, —NH(C₁₋₆-alkyl), —N(C₁₋₆-alkyl)₂,—C₁₋₆-alkylene-NH(C₁₋₆-alkyl), —C₁₋₆-alkylene-N(C₁₋₆-alkyl)₂,C₃₋₈-cycloalkyl, heterocyclyl, aryl, heteroaryl, or a heterocyclyl, arylor heteroaryl group bonded via a C₁₋₆-alkylene group, C₂₋₆-alkenylenegroup or C₂₋₆-alkynylene group; wherein said C₁₋₆-alkyl, C₁₋₆-alkylene,C₂₋₆-alkenylene, C₂₋₆-alkynylene, C₃₋₈-cycloalkyl, heterocyclyl, aryland heteroaryl groups each may be unsubstituted or mono- orpoly-substituted with identical or different substituents; and saidC₁₋₆-alkyl, C₁₋₆-alkylene, C₂₋₆-alkenylene, and C₂₋₆-alkynylene groupseach may be branched or unbranched; or a physiologically compatible saltthereof.
 2. A compound as claimed in claim 1, wherein said compound isin the form of an isolated stereoisomer.
 3. A compound as claimed inclaim 1, wherein said compound is in the form of a mixture ofstereoisomers in any mixing ratio.
 4. A compound as claimed in claim 3,wherein said mixture is a racemic mixture.
 5. A compound as claimed inclaim 1, wherein m and n each independently denote 0, 1 or 2; p denotes1 or 2; Q denotes —O— or —CH₂—; X denotes N or CR⁵; Y denotes N or CR⁶;Z denotes N or CR⁷; R¹ denotes aryl, heteroaryl, or an aryl orheteroaryl group bonded via a C₁₋₆-alkylene group; R² and R³ eachindependently denote H, C₁₋₆-alkyl, aryl, heteroaryl, or an aryl orheteroaryl group bonded via a C₁₋₆-alkylene group, C₂₋₆-alkenylene groupor C₂₋₆-alkynylene group; R⁴ denotes H, halogen, CN, NO₂, C₁₋₆-alkyl,aryl, heteroaryl, an aryl or heteroaryl group bonded via a C₁₋₆-alkylenegroup, C₂₋₆-alkenylene group or C₂₋₆-alkynylene group; R⁵, R⁶ and R⁷each independently denote H, halogen, CN, C₁₋₆-alkyl, —NH(C₁₋₆-alkyl),—N(C₁₋₆-alkyl)₂, —C₁₋₆-alkylene-NH(C₁₋₆-alkyl),—C₁₋₆-alkylene-N(C₁₋₆-alkyl)₂, C₃₋₈-cycloalkyl, heterocyclyl, aryl,heteroaryl, or a heterocyclyl, aryl or heteroaryl group bonded via aC₁₋₆-alkylene group, C₂₋₆-alkenylene group or C₂₋₆-alkynylene group;wherein said C₁₋₆-alkyl, C₁₋₆-alkylene, C₂₋₆-alkenylene,C₂₋₆-alkynylene, C₃₋₈-cycloalkyl, heterocyclyl, aryl and heteroarylgroups each may be unsubstituted or mon- or poly-substituted withidentical or different substituents; and said C₁₋₆-alkyl, C₁₋₆-alkylene,C₂₋₆-alkenylene and C₂₋₆-alkynylene groups each may be branched orunbranched; a substituted alkyl, alkylene, alkenylene, alkynylene orcycloalkyl group may be mono- or poly-substituted with identical ordifferent substituents selected from the group consisting of F, Cl, Br,I, CN, NH₂, NH—C₁₋₆-alkyl, NH—C₁₋₆-alkylene-OH, C₁₋₆-alkyl,N(C₁₋₆-alkyl)₂, N(C₁₋₆-alkylene-OH)₂, NO₂, SH, S—C₁₋₆-alkyl, S-benzyl,O—C₁₋₆-alkyl, OH, O—C₁₋₆-alkylene-OH, ═O, O-benzyl, C(═O)C₁₋₆-alkyl,CO₂H, CO₂—C₁₋₆-alkyl and benzyl; a substituted heterocyclyl group may bemonosubstituted or polysubstituted with identical or differentsubstituents selected from the group consisting of F, Cl, Br, I, —CN,NH₂, NH—C₁₋₆-alkyl, NH—C₁₋₆-alkylene-OH, C₁₋₆-alkyl, N(C₁₋₆-alkyl)₂,N(C₁₋₆-alkylene-OH)₂, pyrrolinyl, piperazinyl, morpholinyl, NO₂, SH,S—C₁₋₆-alkyl, S-benzyl, O—C₁₋₆-alkyl, OH, O—C₁₋₆-alkylene-OH, ═O,O-benzyl, C(═O)C₁₋₆-alkyl, CO₂H, CO₂—C₁₋₆-alkyl and benzyl; and asubstituted aryl or heteroaryl group may be mono- or poly-substitutedwith identical or different substituents selected from the groupconsisting of F, Cl, Br, I, CN, NH₂, NH—C₁₋₆-alkyl, NH—C₁₋₆-alkylene-OH,N(C₁₋₆-alkyl)₂, N(C₁₋₆-alkylene-OH)₂, NH-aryl¹, N(aryl¹)₂,N(C₁₋₆-alkyl)aryl¹, pyrrolinyl, piperazinyl, morpholinyl, NO₂, SH,S—C₁₋₆-alkyl, OH, O—C₁₋₆-alkyl, O—C₁₋₆-alkyl-OH, C(═O)C₁₋₆-alkyl,NHSO₂C₁₋₆-alkyl, NHCOC₁₋₆-alkyl, CO₂H, CH₂SO₂-phenyl, CO₂—C₁₋₆-alkyl,OCF₃, CF₃, —O—CH₂—O—, —O—CH₂—CH₂—O—, —O—C(CH₃)₂—CH₂—, unsubstitutedC₁₋₆-alkyl, pyrrolidinyl, imidazolyl, piperidinyl, benzyloxy, phenoxy,phenyl, pyridinyl, —C₁₋₃-alkylene-aryl¹, benzyl, thienyl and furyl,wherein aryl¹ denotes phenyl, furyl, thienyl or pyridinyl.
 6. A compoundas claimed in claim 1, wherein R¹ denotes a phenyl, naphthyl, indolyl,benzofuranyl, benzothiophenyl, benzooxazolyl, benzooxadiazolyl,pyrrolyl, furanyl, thienyl, pyridinyl, pyridazinyl, pyrimidinyl,pyrazinyl, imidazothiazolyl, carbazolyl, dibenzofuranyl ordibenzothiophenyl group which may be unsubstituted or mono- orpoly-substituted with identical or different substituents selected fromthe group consisting of —O—C₁₋₃-alkyl, C₁₋₆-alkyl, F, Cl, Br, I, CF₃,OCF₃, OH, SH, phenyl, naphthyl, furyl, thienyl and pyridinyl.
 7. Acompound as claimed in claim 6, wherein R¹ denotes a phenyl, naphthyl,benzothiophenyl, benzooxadizolyl, thiophenyl, pyridinyl,imidazothiazolyl or dibenzofuranyl group which may be unsubstituted ormono- or poly-substituted with identical or different substituentsselected from the group consisting of —O—C₁₋₃-alkyl, C₁₋₆-alkyl, F, Cl,Br, I, CF₃, OCF₃, OH, SH, phenyl, naphthyl, furyl, thienyl andpyridinyl,
 8. A compound as claimed in claim 1, wherein R¹ denotesphenyl or naphthyl which may be unsubstituted or monosubstituted oridentically or differently polysubstituted with substituents selectedfrom the group consisting of methyl, methoxy, CF₃, F, Cl, and Br.
 9. Acompound as claimed in claim 1, wherein R² denotes H, C₁₋₆-alkyl, aryl,or an aryl group bonded via a C₁₋₆-alkylene group, C₂₋₆-alkenylene groupor C₂₋₆-alkynylene group, wherein said aryl may be unsubstituted ormonosubstituted or polysubstituted with identical or differentsubstituents selected from the group consisting of C₁₋₆-alkyl,C₁₋₆-alkyl-O—, F, Cl, Br, I, CF₃, OCF₃, OH and SH.
 10. A compound asclaimed in claim 9, wherein R² denotes H, C₁₋₆-alkyl, phenyl, or aphenyl group bonded via a C₁₋₆-alkylene group, wherein said phenyl maybe unsubstituted or monosubstituted or polysubstituted with identical ordifferent substituents selected from the group consisting of methyl,ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl,methoxy, F, Cl, Br, I, CF₃, OCF₃ and OH.
 11. A compound as claimed inclaim 1, wherein R³ denotes H, C₁₋₆-alkyl, aryl, or an aryl group bondedvia a C₁₋₆-alkylene group, C₂₋₆-alkylene group or C₃₋₆-alkynylene group,wherein said aryl may be unsubstituted or mono- or poly-substituted withidentical or different substituents selected from the group consistingof C₁₋₆-alkyl, C₁₋₆-alkyl-O—, F, Cl, Br, I, CF₃, OCF₃, OH and SH.
 12. Acompound as claimed in claim 11, wherein R³ denotes H or phenyl whichmay be unsubstituted or mono- or poly-substituted with identical ordifferent substituents selected from the group consisting of methyl,ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl,methoxy, F, Cl, Br, I, CF₃, OCF₃ and OH.
 13. A compound as claimed inclaim 1, wherein p is
 1. 14. A compound as claimed in claim 1, whereinif Q=—O—, then m and n are each 1, and if Q=—CH₂—, then the sum m+n=0or
 1. 15. A compound as claimed in claim 1, wherein R⁴ denotes H,C₁₋₆-alkyl, aryl, heteroaryl, or an aryl or heteroaryl group bonded viaa C₁₋₆-alkylene group, C₂₋₆-alkenylene group or C₂₋₆-alkynylene group,wherein the aryl or heteroaryl may be unsubstituted or monosubstitutedor identically or differently polysubstituted with substituents selectedfrom the group consisting of O—C₁₋₃-alkyl, unsubstituted C₁₋₆-alkyl, F,Cl, Br, I, CF₃, OCF₃, OH and SH.
 16. A compound as claimed in claim 15,wherein R⁴ said aryl or heteroaryl is selected from the group consistingof phenyl, naphthyl, pyridinyl, thienyl and furyl.
 17. A compound asclaimed in claim 1, wherein R⁵, R⁶ and R⁷ each independently denote H,halogen, C₁₋₆-alkyl, —N(C₁₋₆-alkyl)₂, —C₁₋₆-alkylene-N(C₁₋₆-alkyl)₂, 5-,6- or 7-membered heterocyclyl, 5- or 6-membered heteroaryl, or a 5- or6-membered heteroaryl or 5-,6- or 7-membered heterocyclyl group bondedvia a C₁₋₆-alkylene group, wherein said heterocyclyl comprises one ortwo identical or different heteroatoms selected from the groupconsisting of N and O and is unsubstituted or monosubstituted oridentically or differently polysubstituted with C₁₋₆-alkyl.
 18. Acompound as claimed in claim 1, wherein: m and n each independentlydenote 0 or 1; p is 1; Q denotes —O— or —CH₂; X denotes N or CR⁵; Ydenotes N or CR⁶; Z denotes N or CR⁷; R¹ denotes phenyl, naphthyl,indolyl, benzofuranyl, benzothiophenyl, benzooxazolyl, benzooxadiazolyl,pyrrolyl, furanyl, thienyl, pyridinyl, pyridazinyl, pyrimidinyl,pyrazinyl, imidazothiazolyl, carbazolyl, dibenzofuranyl ordibenzothiophenyl, which may be unsubstituted or mono- orpoly-substituted with identical or different substituents selected fromthe group consisting of —O—C₁₋₃-alkyl, C₁₋₆-alkyl, F, Cl, Br, I CF₃,OCF₃, OH, SH, phenyl, naphthyl, furyl, thienyl and pyridinyl; R² and R³each independently denote H, C₁₋₆-alkyl, aryl, or an aryl group bondedvia a C₁₋₆-alkylene group, C₂₋₆-alkenylene group or C₂₋₆-alkynylenegroup, wherein said aryl may be unsubstituted or mono- orpoly-substituted with identical or different substituents selected fromthe group consisting of C₁₋₆-alkyl, C₁₋₆-alkyl-O—, F, Cl, Br, I, CF₃,OCF₃, OH and SH; R⁴ denotes H, C₁₋₆-alkyl, aryl, heteroaryl, or an arylor heteroaryl group bonded via a C₁₋₆-alkylene group, C₂₋₆-alkenylenegroup or C₂₋₆-alkynylene group, wherein said aryl or heteroaryl may beunsubstituted or monosubstituted or identically or differentlypolysubstituted with substituents selected from the group consisting ofO—C₁₋₃-alkyl, unsubstituted C₁₋₆-alkyl, F, Cl, Br, I, CF₃, OCF₃, OH andSH; and R⁵, R⁶ and R⁷ each independently denote H, halogen, C₁₋₆-alkyl,—N(C₁₋₆-alkyl)₂, —C₁₋₆-alkylene-N(C₁₋₆-alkyl)₂, 5-membered or 6-memberedheterocyclyl, 5- or 6-membered heteroaryl, or a 5- or 6-memberedheteroaryl or a 5- or 6-membered heterocyclyl group bonded via aC₁₋₆-alkylene group, wherein the heterocyclyl comprises 1 or 2 identicalor different heteroatoms selected from the group consisting of N and Oand may be unsubstituted or monosubstituted or identically ordifferently polysubstituted with C₁₋₆-alkyl.
 19. A compound as claimedin claim 18, wherein: R¹ denotes phenyl, naphthyl, benzothiophenyl,benzooxadiazolyl, thiophenyl, pyridinyl, imidazothiazolyl ordibenzofuranyl; and R⁴ denotes aryl, heteroaryl, or an aryl orheteroaryl group bonded via a C₁₋₆-alkylene group, C₂₋₆-alkenylene groupor C₂₋₆-alkynylene group, wherein said aryl or heteroaryl is selectedfrom the group consisting of phenyl, naphthyl, pyridinyl, thienyl andfuryl.
 20. A compound as claimed in claim 1, wherein: if Q=—O—, then mand n each denote 1, and if Q=—CH₂—; then the sum m+n=0 or 1; p is 1; R¹denotes phenyl or naphthyl, which each may be unsubstituted ormonosubstituted or identically or differently polysubstituted withsubstituents selected from the group consisting of methyl, methoxy, CF₃,F, Cl and Br; R² denotes H, C₁₋₆-alkyl, phenyl, or a phenyl group bondedvia a C₁₋₆-alkylene group, wherein said phenyl may be unsubstituted ormono- or poly-substituted with identical or different substituentsselected from the group consisting of methyl, ethyl, n-propyl,iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, methoxy, F, Cl,Br, I, CF₃, OCF₃ and OH; R³ denotes H or phenyl which may beunsubstituted or mono- or poly-substituted with identical or differentsubstituents selected from the group consisting of methyl, ethyl,n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl,methoxy, F, Cl, Br, I, CF₃, OCF₃ and OH; R⁴ denotes H, C₁₋₆-alkyl,phenyl, furyl, thienyl, pyridinyl, or a phenyl, furyl, thienyl orpyridinyl group bonded via a C₁₋₃-alkylene group, wherein said phenyl,furyl, thienyl or pyridinyl may be unsubstituted or monosubstituted oridentically or differently polysubstituted with substituents selectedfrom the group consisting of —O—C₁₋₃-alkyl, unsubstituted C₁₋₆-alkyl, F,Cl, Br, I, CF₃, OCF₃, OH, SH; R⁵ denotes H; R⁶ denotes H or a groupselected from the group consisting of

wherein R⁸ and R⁹ each independently denote a C₁₋₆-alkyl group, j is 1,2 or 3; and M¹, M² and M³ each independently denote N or CH, wherein oneof M¹, M² and M³ represents N, and the other two of M¹, M² and M³ eachrepresent CH; R⁷ denotes H, F, Cl, Br, I, C₁₋₆-alkyl, or a groupselected from the group consisting of:

wherein R⁸ and R⁹ each independently denote a C₁₋₆-alkyl group; j is 1,2 or 3; and M¹, M² und M³ each independently denote N or CH, wherein oneof M¹, M² and M³ represents N, and the other two of M¹, M² and M³ eachrepresent CH.
 21. A compound as claimed in claim 1, wherein m=1, n=1,and Q denotes —O—; or m=1, n=0, and Q denotes —CH₂—; or m=0, n=1, and Qdenotes —CH₂—; or m=0, n=0, and Q denotes —CH₂—; p denotes 1; X denotesN or CR⁵; Y denotes N or CR⁶; Z denotes N or CR⁷; R¹ denotes phenyl ornaphthyl, which each may be unsubstituted or monosubstituted oridentically or differently disubstituted, trisubstituted,tetrasubstituted or pentasubstituted with substituents selected from thegroup consisting of methyl, methoxy, CF₃, F, Cl and Br; R² denotes H,methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl,tert-butyl, phenyl, or a phenyl group bonded via a —CH₂—, —(CH₂)₂— or—(CH₂)₃— group, wherein said phenyl may be unsubstituted ormonosubstituted, disubstituted, trisubstituted, tetrasubstituted orpentasubstituted with identical or different substituents selected fromthe group consisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl,iso-butyl, sec-butyl, tert-butyl, methoxy, F, Cl, Br, I, CF₃, OCF₃ andOH; R³ denotes H or unsubstituted phenyl; R⁴ denotes H, methyl, ethyl,n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, phenyl,furyl, thienyl, pyridinyl, or a phenyl, furyl, thienyl or pyridinylgroup bonded via a —(CH₂)—, —(CH₂)₂— or —(CH₂)₃— group, wherein saidphenyl, furyl, thienyl or pyridinyl may be unsubstituted ormonosubstituted, disubstituted or trisubstituted with substituentsindependently selected from the group consisting of methoxy, ethoxy,n-propoxy, iso-propoxy, methyl, ethyl, n-propyl, iso-propyl, n-butyl,iso-butyl, sec-butyl, tert-butyl, F, Cl, Br, I, CF₃, OCF₃, OH and SH; R⁵denotes H; R⁶ denotes H or a group selected from the group consistingof:

wherein R⁸ and R⁹ each denote a methyl group; j is 1, 2 or 3, and M¹, M²und M³ each independently denote N or CH, wherein one of M¹, M² and M³represents N, and the other two of M¹, M² and M³ each represent CH; andR⁷ denotes H, F, Cl, Br, I, methyl, ethyl, n-propyl, iso-propyl,n-butyl, iso-butyl, sec-butyl, tert-butyl or a group selected from thegroup consisting of:

wherein R⁸ and R⁹ each denote a methyl group; j is 1, 2 or 3; and M¹, M²und M³ each independently denote N or CH, wherein one of M¹, M² and M³represents N, and the other two of M¹, M² and M³ each represent CH. 22.A compound as claimed in claim 1, wherein: X denotes N; Y denotes CR⁶,and Z denotes CR⁷; or X denotes N; Y denotes N, and Z denotes CR⁷; or Xdenotes CR⁵; Y denotes CR⁶, and Z denotes CR⁷.
 23. A compound as claimedin claim 1, selected from the group consisting of: (1)N-(2-(2-(6-((dimethylamino)methyl)-1-phenyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,3,6-tetramethylbenzenesulfonamide,(2)4-methoxy-N,2,6-trimethyl-N-(2-(2-oxo-2-(2-(piperidin-1-ylmethyl)-5,6-dihydroimidazo-yl)ethoxy)ethyl)benzenesulfonamide,(3)N-(2-(2-(5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,6-trimethylbenzenesulfonamide,(4)(R)—N-(3-oxo-1-phenyl-3-(2-(piperidin-1-ylmethyl)-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)propyl)naphthalene-2-sulfonamide,(5)(R)—N-(3-(3-chloro-2-(piperidin-1-ylmethyl)-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)-3-oxo-1-phenylpropyl)naphthalene-2-sulfonamide,(6)N-(2-(2-(3-chloro-2-(piperidin-1-ylmethyl)-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,6-trimethylbenzenesulfonamide,(7)4-methoxy-N,2,6-trimethyl-N-(2-(2-(6-(morpholinomethyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)benzenesulfonamide,(8)N-(3-oxo-1-phenyl-3-(6-(pyrrolidin-1-ylmethyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)propyl)naphthalene-2-sulfonamide,(9)4-methoxy-N,2,6-trimethyl-N-(2-(2-(6-((4-methylpiperazin-1-yl)methyl)-3,4-dihydropyrrolo-[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)-ethyl)benzenesulfonamide,(10)N-(3-(6-(morpholinomethyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-3-oxo-1-phenylpropyl)naphthalene-2-sulfonamide,(11)4-methoxy-N,2,6-trimethyl-N-(2-(2-oxo-2-(6-(pyrrolidin-1-ylmethyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide,(12)4-methoxy-N,2,6-trimethyl-N-(2-(2-(6-(3-(4-methylpiperazin-1-yl)propyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)benzenesulfonamide,(13)N-(3-(6-(3-(4-methylpiperazin-1-yl)propyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-3-oxo-1-phenylpropyl)naphthalin-2-sulfonamide,(14)N-(2-(2-(6-((dimethylamino)methyl)-1-phenyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,6-trimethylbenzenesulfonamide,(15)4-methoxy-N,2,6-trimethyl-N-(2-(2-oxo-2-(1-phenyl-6-(pyrrolidin-1-ylmethyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide,(16)4-methoxy-N,2,6-trimethyl-N-(2-(2-oxo-2-(1-phenyl-6-(piperidin-1-ylmethyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide,(17)N-(2-(2-(6-((dimethylamino)methyl)-1-(thiophen-2-yl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,6-trimethylbenzene-sulfonamide,(18)N-(2-(2-(1-tert-butyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-N-isobutyl-4-methoxy-2,3,6-trimethylbenzenesulfonamide,(19)N-isobutyl-4-methoxy-2,3,6-trimethyl-N-(2-(2-oxo-2-(1-(pyridin-3-yl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzolsulfonamide,(20)N-(2-(2-(1-(6-chloropyridin-3-yl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-N-isobutyl-4-methoxy-2,3,6-trimethylbenzenesulfonamide,(21)N-(2-(2-(5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)-2-oxoethoxy)ethyl)-N-isobutyl-4-methoxy-2,3,6-trimethylbenzenesulfonamide,(22)N-isobutyl-4-methoxy-N-(2-(2-(1-(4-methoxyphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-2,3,6-trimethylbenzenesulfonamide,(23)N-isobutyl-4-methoxy-2,3,6-trimethyl-N-(2-(2-oxo-2-(1-phenyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide,(24)N-(2-(2-(1-(3-fluorophenyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-N-isobutyl-4-methoxy-2,3,6-trimethylbenzenesulfonamide,(25)N-isobutyl-4-methoxy-2,3,6-trimethyl-N-(2-(2-oxo-2-(1-(thiophen-2-yl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide,(26)N-isobutyl-4-methoxy-N-(2-(2-(1-(3-methoxyphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-2,3,6-trimethylbenzenesulfonamide,(27)N-(2-(2-(1-tert-butyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,3,5-tetramethylbenzenesulfonamide,(28)4-methoxy-N,2,3,5-tetramethyl-N-(2-(2-(1-methyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)benzenesulfonamide,(29)4-methoxy-N,2,3,5-tetramethyl-N-(2-(2-oxo-2-(1-(pyridin-3-yl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide,(30)N-(2-(2-(1-(6-chloropyridin-3-yl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,3,5-tetramethylbenzenesulfonamide,(31)4-methoxy-N-(2-(2-(1-(4-methoxyphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-N,2,3,5-tetramethylbenzenesulfonamide,(32)4-methoxy-N,2,3,5-tetramethyl-N-(2-(2-oxo-2-(1-phenyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide,(33)N-(2-(2-(1-(3,4-difluorophenyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,3,5-tetramethylbenzenesulfonamide,(34)N-(2-(2-(1-(3,4-dimethylphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,3,5-tetramethylbenzenesulfonamide,(35)N-(2-(2-(1-(3-fluorophenyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,3,5-tetramethylbenzenesulfonamide,(36)4-methoxy-N,2,3,5-tetramethyl-N-(2-(2-oxo-2-(1-(thiophen-2-yl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide,(37)4-methoxy-N,2,3,5-tetramethyl-N-(2-(2-oxo-2-(1-(3-(trifluoromethyl)phenyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide,(38)4-methoxy-N-(2-(2-(1-(3-methoxyphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-N,2,3,5-tetramethylbenzenesulfonamide,(39)N-(2-(2-(1-(2-fluoro-4-(trifluoromethyl)phenyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,3,5-tetramethyl-benzenesulfonamide,(40)N-benzyl-4-methoxy-2,3,6-trimethyl-N-(2-(2-(1-methyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)benzenesulfonamide,(41)N-benzyl-4-methoxy-2,3,6-trimethyl-N-(2-(2-oxo-2-(1-(pyridin-3-yl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide,(42)N-benzyl-N-(2-(2-(1-(6-chloropyridin-3-yl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-2,3,6-trimethylbenzenesulfonamide,(43)N-benzyl-N-(2-(2-(5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-2,3,6-trimethylbenzenesulfonamide,(44)N-benzyl-N-(2-(2-(1-tert-butyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-2,6-dimethylbenzenesulfonamide,(45)N-benzyl-4-methoxy-2,6-dimethyl-N-(2-(2-(1-methyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)benzenesulfonamide,(46)N-benzyl-N-(2-(2-(5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-2,6-dimethylbenzenesulfonamide,(47)N-benzyl-4-methoxy-N-(2-(2-(1-(4-methoxyphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-2,6-dimethylbenzenesulfonamide,(48)N-benzyl-4-methoxy-2,6-dimethyl-N-(2-(2-oxo-2-(1-phenyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide,(49)N-benzyl-N-(2-(2-(1-(3,4-dimethylphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-2,6-dimethylbenzenesulfonamide,(50)N-benzyl-4-methoxy-2,6-dimethyl-N-(2-(2-oxo-2-(1-(thiophen-2-yl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide,(51)N-benzyl-N-(2-(2-(1-(4-tert-butylphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-2,6-dimethylbenzenesulfonamide,(52)N-(2-(2-(1-tert-butyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,6-trimethylbenzenesulfonamide,(53)4-methoxy-N,2,6-trimethyl-N-(2-(2-(1-methyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)benzenesulfonamide,(54)4-methoxy-N,2,6-trimethyl-N-(2-(2-oxo-2-(1-(pyridin-3-yl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide,(55)N-(2-(2-(1-(6-chloropyridin-3-yl)-3,4-dihydropyrrolo-[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,6-trimethylbenzenesulfonamide,(56)N-(2-(2-(5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,6-trimethylbenzenesulfonamide,(57)N-(2-(2-(1-(3,4-difluorophenyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,6-trimethylbenzenesulfonamide,(58)N-(2-(2-(1-(3,4-dimethylphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,6-trimethylbenzenesulfonamide,(59)N-(2-(2-(1-(3-fluorophenyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,6-trimethylbenzenesulfonamide,(60)4-Methoxy-N,2,6-trimethyl-N-(2-(2-oxo-2-(1-(thiophen-2-yl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide,(61)4-methoxy-N,2,6-trimethyl-N-(2-(2-oxo-2-(1-(3-(trifluoromethyl)phenyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide,(62)4-methoxy-N-(2-(2-(1-(3-methoxyphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-N,2,6-trimethylbenzenesulfonamide,(63)N-(2-(2-(1-(2-fluoro-4-(trifluoromethyl)phenyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,6-trimethylbenzene-sulfonamide,(64)N-(2-(2-(1-(4-tert-butylphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,6-trimethylbenzenesulfonamide,(65)N-(2-(2-(1-tert-butyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-N,2,4,6-tetramethylbenzenesulfonamide,(66)N-2,4,6-tetramethyl-N-(2-(2-(1-methyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)benzenesulfonamide,(67)N,2,4,6-tetramethyl-N-(2-(2-oxo-2-(1-(pyridin-3-yl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide,(68)N-(2-(2-(1-(6-chloropyridin-3-yl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-N,2,4,6-tetramethylbenzenesulfonamide,(69)N-(2-(2-(1-(4-methoxyphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-N,2,4,6-tetramethylbenzenesulfonamide,(70)N,2,4,6-tetramethyl-N-(2-(2-oxo-2-(1-phenyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide,(71)N-(2-(2-(1-(3,4-difluorophenyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-N,2,4,6-tetramethylbenzenesulfonamide,(72)N-(2-(2-(1-(3,4-dimethylphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-N,2,4,6-tetramethylbenzenesulfonamide,(73)N-(2-(2-(1-(3-fluorophenyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-N,2,4,6-tetramethylbenzenesulfonamide,(74)N,2,4,6-tetramethyl-N-(2-(2-oxo-2-(1-(thiophen-2-yl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide,(75)N,2,4,6-tetramethyl-N-(2-(2-oxo-2-(1-(3-(trifluoromethyl)phenyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide,(76)N-(2-(2-(1-(3-methoxyphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-N,2,4,6-tetramethylbenzenesulfonamide,(77)N-(2-(2-(1-(2-fluoro-4-(trifluoromethyl)phenyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-N,2,4,6-tetramethylbenzenesulfonamide,(78)N-(2-(2-(1-(4-tert-butylphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-N,2,4,6-tetramethylbenzenesulfonamide,(79)N-(2-(2-(1-tert-butyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,3,6-tetramethylbenzenesulfonamide,(80)4-methoxy-N,2,3,6-tetramethyl-N-(2-(2-(1-methyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)benzenesulfonamide,(81)4-methoxy-N,2,3,6-tetramethyl-N-(2-(2-oxo-2-(1-(pyridin-3-yl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide,(82)N-(2-(2-(1-(6-chloropyridin-3-yl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,3,6-tetramethylbenzenesulfonamide,(83)4-methoxy-N-(2-(2-(1-(4-methoxyphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-N,2,3,6-tetramethylbenzenesulfonamide,(84)4-methoxy-N,2,3,6-tetramethyl-N-(2-(2-oxo-2-(1-phenyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide,(85)N-(2-(2-(1-(3,4-difluorophenyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,3,6-tetramethylbenzenesulfonamide,(86)N-(2-(2-(1-(3,4-dimethylphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,3,6-tetramethylbenzenesulfonamide,(87)N-(2-(2-(1-(3-fluorophenyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,3,6-tetramethylbenzenesulfonamide,(88)4-methoxy-N,2,3,6-tetramethyl-N-(2-(2-oxo-2-(1-(thiophen-2-yl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide,(89)4-methoxy-N-(2-(2-(1-(3-methoxyphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-N,2,3,6-tetramethylbenzenesulfonamide,(90)N-(2-(2-(1-(4-tert-butylphenyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,3,6-tetramethylbenzenesulfonamide,(91)N-(2-(2-(6-((dimethylamino)methyl)-1-phenyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-N-isobutyl-4-methoxy-2,3,6-trimethylbenzene-sulfonamide,(92)N-isobutyl-4-methoxy-2,3,6-trimethyl-N-(2-(2-oxo-2-(1-phenyl-6-(pyrrolidin-1-ylmethyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzene-sulfonamide,(93)N-isobutyl-4-methoxy-2,3,6-trimethyl-N-(2-(2-oxo-2-(1-phenyl-6-(piperidin-1-ylmethyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzene-sulfonamide,(94)N-isobutyl-4-methoxy-2,3,6-trimethyl-N-(2-(2-(6-(morpholinomethyl)-1-phenyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)benzene-sulfonamide,(95)N-(2-(2-(1-benzyl-6-((dimethylamino)methyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-N-isobutyl-4-methoxy-2,3,6-trimethylbenzene-sulfonamide,(96)N-(2-(2-(6-((dimethylamino)methyl)-1-phenethyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-N-isobutyl-4-methoxy-2,3,6-trimethyl-benzenesulfonamide,(97)N-(2-(2-(1-butyl-6-((dimethylamino)methyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-N-isobutyl-4-methoxy-2,3,6-trimethylbenzene-sulfonamide,(98)N-(2-(2-(6-((dimethylamino)methyl)-1-(thiophen-2-yl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-N-isobutyl-4-methoxy-2,3,6-trimethyl-benzenesulfonamide,(99)N-(2-(2-(6-((dimethylamino)methyl)-1-ethyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-N-isobutyl-4-methoxy-2,3,6-trimethylbenzene-sulfonamide,(100)N-(2-(2-(1-ethyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-N-isobutyl-4-methoxy-2,3,6-trimethylbenzenesulfonamide,(101)N-isobutyl-4-methoxy-2,3,6-trimethyl-N-(2-(2-oxo-2-(1-propyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide,(102)N-isobutyl-N-(2-(2-(1-isopropyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-2,3,6-trimethylbenzenesulfonamide,(103)N-(2-(2-(1-ethyl-6-methyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-N-isobutyl-4-methoxy-2,3,6-trimethylbenzenesulfonamide,(104)N-isobutyl-N-(2-(2-(1-isopropyl-6-methyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-2,3,6-trimethylbenzenesulfonamide,(105)N-(2-(2-(6-((dimethylamino)methyl)-1-phenyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,3,5-tetramethyl-benzenesulfonamide,(106)4-methoxy-N,2,3,5-tetramethyl-N-(2-(2-oxo-2-(1-phenyl-6-(pyrrolidin-1-ylmethyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzene-sulfonamide,(107)4-methoxy-N,2,3,5-tetramethyl-N-(2-(2-oxo-2-(1-phenyl-6-(piperidin-1-ylmethyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzene-sulfonamide,(108)4-methoxy-N,2,3,5-tetramethyl-N-(2-(2-(6-(morpholinomethyl)-1-phenyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)benzenesulfonamide,(109)N-(2-(2-(1-benzyl-6-((dimethylamino)methyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,3,5-tetramethyl-benzenesulfonamide,(110)N-(2-(2-(6-((dimethylamino)methyl)-1-phenethyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,3,5-tetramethyl-benzenesulfonamide,(111)N-(2-(2-(1-butyl-6-((dimethylamino)methyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,3,5-tetramethylbenzenesulfonamide,(112)N-(2-(2-(6-((dimethylamino)methyl)-1-(thiophen-2-yl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,3,5-tetramethyl-benzenesulfonamide,(113)N-(2-(2-(6-((dimethylamino)methyl)-1-ethyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,3,5-tetramethylbenzenesulfonamide,(114)N-(2-(2-(1-ethyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,3,5-tetramethylbenzenesulfonamide,(115)4-methoxy-N,2,3,5-tetramethyl-N-(2-(2-oxo-2-(1-propyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide,(116)N-benzyl-4-methoxy-2,3,6-trimethyl-N-(2-(2-oxo-2-(1-phenyl-6-(pyrrolidin-1-ylmethyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzene-sulfonamide,(117)N-benzyl-4-methoxy-2,3,6-trimethyl-N-(2-(2-(6-(morpholinomethyl)-1-phenyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)benzene-sulfonamide,(118)N-benzyl-N-(2-(2-(1-benzyl-6-((dimethylamino)methyl)-3,4-dihydropyrrolo-[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-2,3,6-trimethyl-benzenesulfonamide,(119)N-benzyl-N-(2-(2-(6-((dimethylamino)methyl)-1-phenethyl-3,4-dihydropyrrolo-[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-2,3,6-trimethyl-benzenesulfonamide,(120)N-benzyl-N-(2-(2-(1-butyl-6-((dimethylamino)methyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)-ethyl)-4-methoxy-2,3,6-trimethylbenzenesulfonamide,(121)N-benzyl-N-(2-(2-(6-((dimethylamino)methyl)-1-(thiophen-2-yl)-3,4-dihydro-pyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-2,3,6-trimethyl-benzenesulfonamide,(122)N-benzyl-N-(2-(2-(6-((dimethylamino)methyl)-1-ethyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethyl)ethyl)-4-methoxy-2,3,6-trimethylbenzene-sulfonamide,(123)N-benzyl-4-methoxy-2,3,6-trimethyl-N-(2-(2-oxo-2-(1-propyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide,(124)N-benzyl-N-(2-(2-(1-isopropyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-2,3,6-trimethylbenzenesulfonamide,(125)N-benzyl-4-methoxy-2,6-dimethyl-N-(2-(2-oxo-2-(1-phenethyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide,(126)N-benzyl-N-(2-(2-(6-((dimethylamino)methyl)-1-phenyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-2,6-dimethylbenzenesulfonamide,(127)N-benzyl-4-methoxy-2,6-dimethyl-N-(2-(2-oxo-2-(1-phenyl-6-(pyrrolidin-1-ylmethyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide,(128)N-benzyl-4-methoxy-2,6-dimethyl-N-(2-(2-oxo-2-(1-phenyl-6-(piperidin-1-ylmethyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide,(129)N-benzyl-N-(2-(2-(1-benzyl-6-((dimethylamino)methyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2-(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-2,6-dimethylbenzenesulfonamide,(130)N-benzyl-N-(2-(2-(6-((dimethylamino)methyl)-1-(thiophen-2-yl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-2,6-dimethylbenzenesulfonamide,(131)N-benzyl-N-(2-(2-(6-((dimethylamino)methyl)-1-ethyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-2,6-dimethylbenzenesulfonamide,(132)N-benzyl-N-(2-(2-(1-ethyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-2,6-dimethylbenzenesulfonamide,(133)4-methoxy-N,2,6-trimethyl-N-(2-(2-oxo-2-(1-phenethyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide,(134)N-(2-(2-(1-butyl-6-((dimethylamino)methyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,6-trimethylbenzenesulfonamide,(135)N-(2-(2-(1-ethyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,6-trimethylbenzenesulfonamide,(136)4-methoxy-N,2,6-trimethyl-N-(2-(2-oxo-2-(1-propyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide,(137)N-(2-(2-(1-isopropyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,6-trimethylbenzenesulfonamide,(138)N-(2-(2-(1-ethyl-6-methyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,6-trimethylbenzenesulfonamide,(139)N-(2-(2-(6-((dimethylamino)methyl)-1-phenyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-N,2,4,6-tetramethylbenzenesulfonamide,(140)N,2,4,6-tetramethyl-N-(2-(2-oxo-2-(1-phenyl-6-(pyrrolidin-1-ylmethyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide,(141)N,2,4,6-tetramethyl-N-(2-(2-oxo-2-(1-phenyl-6-(piperidin-1-ylmethyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide,(142)N,2,4,6-tetramethyl-N-(2-(2-(6-(morpholinomethyl)-1-phenyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)benzenesulfonamide,(143)N-(2-(2-(1-benzyl-6-((dimethylamino)methyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-N,2,4,6-tetramethylbenzenesulfonamide,(144)N-(2-(2-(6-((dimethylamino)methyl)-1-(thiophen-2-yl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-N,2,4,6-tetramethylbenzenesulfonamide,(145)N-(2-(2-(6-((dimethylamino)methyl)-1-ethyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-N,2,4,6-tetramethylbenzenesulfonamide,(146)N,2,4,6-tetramethyl-N-(2-(2-oxo-2-(1-propyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide,(147)N-(2-(2-(1-isopropyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-N,2,4,6-tetramethylbenzenesulfonamide,(148)4-methoxy-N,2,3,6-tetramethyl-N-(2-(2-oxo-2-(1-phenethyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide,(149)4-methoxy-N,2,3,6-tetramethyl-N-(2-(2-oxo-2-(1-phenyl-6-(piperidin-1-ylmethyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide,(150)4-methoxy-N,2,3,6-tetramethyl-N-(2-(2-(6-(morpholinomethyl)-1-phenyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)benzenesulfonamide,(151)N-(2-(2-(1-benzyl-6-((dimethylamino)methyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,3,6-tetramethylbenzenesulfonamide,(152)N-(2-(2-(1-ethyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,3,6-tetramethylbenzenesulfonamide,(153)N-(2-(2-(1-isopropyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,3,6-tetramethylbenzenesulfonamide,(154)N-benzyl-4-methoxy-2,6-dimethyl-N-(2-(2-oxo-2-(1-propyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide,(155)N-benzyl-N-(2-(2-(1-isopropyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)-4-methoxy-2,6-dimethylbenzenesulfonamide,(156)N-(3-(6-(2-(4-methylpiperazin-1-yl)ethyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-3-oxo-1-phenylpropyl)naphthalin-2-sulfonamide,(157)N-(3-(6-(2-morpholinoethyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-3-oxo-1-phenylpropyl)naphthalin-2-sulfonamide,(158)4-methoxy-N,2,6-trimethyl-N-(2-(2-oxo-2-(6-(2-(pyrrolidin-1-yl)ethyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide,(159)N-(3-oxo-1-phenyl-3-(6-(2-(pyrrolidin-1-yl)ethyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)propyl)naphthalin-2-sulfonamide,(160)4-methoxy-N,2,6-trimethyl-N-(2-(2-(6-(2-(4-methylpiperazin-1-yl)ethyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)benzenesulfonamide,(161)4-methoxy-N,2,6-trimethyl-N-(2-(2-(6-(2-morpholinoethyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-oxoethoxy)ethyl)benzenesulfonamide,(162)N-((1R)-3-(1-Ethyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-3-oxo-1-phenylpropyl)naphthalene-2-sulfonamide,(163)4-Methoxy-N,2,6-trimethyl-N-(2-(2-oxo-2-(3-(piperidin-1-ylmethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)ethoxy)ethyl)benzenesulfonamide,(164)(R)—N-(3-oxo-1-phenyl-3-(3-(piperidin-1-ylmethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)propyl)naphthalene-2-sulfonamide,(165)4-Methoxy-N,2,6-trimethyl-N-(2-(2-oxo-2-(6-(pyridin-4-ylmethyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide,(166)4-Methoxy-N,2,6-trimethyl-N-(2-(2-oxo-2-(6-(pyridin-3-yl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide,(167)N-(3-Oxo-1-phenyl-3-(6-(pyridin-3-yl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)propyl)naphthalene-2-sulfonamide,(168)N-(3-Oxo-1-phenyl-3-(6-(pyridin-4-yl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)propyl)naphthalene-2-sulfonamide,(169)N-(3-Oxo-1-phenyl-3-(6-(pyridin-4-ylmethyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)propyl)naphthalene-2-sulfonamide,(170)4-Methoxy-N,2,6-trimethyl-N-(2-(2-oxo-2-(6-(2-(pyridin-3-yl)ethyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide,(171)N-(3-Oxo-1-phenyl-3-(6-(2-(pyridin-3-yl)ethyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)propyl)naphthalene-2-sulfonamide,(172)4-Methoxy-N,2,6-trimethyl-N-(2-(2-oxo-2-(6-(2-(pyridin-4-yl)ethyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide,(173)N-(3-Oxo-1-phenyl-3-(6-(2-(pyridin-4-yl)ethyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)propyl)naphthalene-2-sulfonamide,(174)4-Methoxy-N,2,6-trimethyl-N-(2-(2-oxo-2-(6-(pyridin-3-ylmethyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide,(175)4-Methoxy-N,2,6-trimethyl-N-(2-(2-oxo-2-(2-(pyridin-4-yl)-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)ethoxy)ethyl)benzenesulfonamide,(176)N-(3-Oxo-1-phenyl-3-(6-(pyridin-3-ylmethyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)propyl)naphthalene-2-sulfonamide,(177)4-Methoxy-N,2,6-trimethyl-N-(2-(2-oxo-2-(6-(pyridin-4-yl)-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethoxy)ethyl)benzenesulfonamide,(178)4-Methoxy-N,2,6-trimethyl-N-(2-(2-oxo-2-(2-(2-(pyridin-4-yl)ethyl)-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)ethoxy)ethyl)benzenesulfonamideand (179)4-Methoxy-N,2,6-trimethyl-N-(2-(2-oxo-2-(2-(pyridin-4-ylmethyl)-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)ethoxy)ethyl)benzenesulfonamideor a physiologically compatible salt thereof.
 24. A pharmaceuticalcomposition comprising a compound as claimed in claim 1, and at leastone pharmaceutically acceptable carrier or auxiliary substance.
 25. Amethod for preparing a compound as claimed in claim 1, said methodcomprising reacting a carboxylic acid corresponding to formula N,wherein m, n, Q, R¹, R² and R³ have the respective meanings given inclaim 1, with an amine corresponding to formula O, wherein p, R⁴, X, Yand Z have the respective meanings given in claim 1, in accordance withthe following reaction scheme:

in the presence of a water-extracting agent, a reagent selected from thegroup consisting of CDI, DCC, TBTU, EDCI, PyBOP and PFPTFA; HOAt orHOBt; and an organic base in an organic solvent, at a temperature from0° C. to the reflux temperature, to yield an amide product correspondingto formula P.
 26. A process as claimed in claim 25, wherein saidwater-extracting agent is sodium or magnesium sulfate or phosphorusoxide; said organic base is diisopropylethyl amine or pyridine, and saidorganic solvent is selected from the group consisting oftetrahydrofuran, dichloromethane, diethyl ether, dioxane,dimethylformamide, and acetonitrile.
 27. A method of treating orinhibiting pain in a subject, said method comprising administering tosaid subject a pharmacologically effective amount of a compound asclaimed in claim
 1. 28. A method as claimed in claim 27, wherein saidpain is acute pain, neuropathic pain or chronic pain.
 29. A method oftreating or inhibiting a condition selected from the group consisting ofpain, migraine, diabetes, diseases of the respiratory tract,inflammatory intestinal diseases, neurological diseases, skininflammation, rheumatic diseases, septic shock, reperfusion syndrome andobesity, or for inhibiting angiogenesis, in a subject, said methodcomprising administering to said subject a pharmacologically effectiveamount of a compound as claimed in claim 1.